O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity

ABSTRACT

O-Aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides of the general structural Formula I: ##STR1## have been prepared from suitable precursors by alkylation and/or arylation at C-3&#34; and/or C-4&#34; of the cyclohexyl ring. These macrolide immunosuppressants are useful in a mammalian host for the treatment of autoimmune diseases, infectious diseases and/or the prevention of rejection of foreign organ transplants. In addition, these macrolide immunosuppressants are useful in the topical treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses. Also, these macrolides are useful in the treatment of reversible obstructive airways disease, particularly asthma; as hair revitalizing agents, especially in the treatment of male pattern alopecia or alopecia senilis; in the reversal of multidrug resistance of tumor cells; in treatment of inflammation of mucosa and blood vessels, gastric ulcers, vascular damage, ischemic bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns; in the treatment of cytomegalovirus infection; and in the treatment of idiopathic thrombocytopenic purpura and Basedow&#39;s disease.

SUMMARY OF THE INVENTION

This application is a continuation-in-part of copending application Ser.No. 07/809,998 filed Dec. 18, 1991, now abandoned, which in turn is acontinuation-in-part of copending application Ser. No. 07/699,407, filedMay 13, 1991, now abandoned.

The present invention is related to O-aryl, O-alkyl, O-alkenyl andO-alkynylmacrolides which are useful in a mammalian host for thetreatment of autoimmune diseases (such as juvenile-onset or recent-onsetdiabetes mellitus, multiple sclerosis, rheumatoid arthritis, liverdisease, posterior uveitis, allergic encephalomyelitis, andglomerulonephritis, infectious diseases and/or the prevention ofrejection of foreign organ transplants, e.g. bone marrow, kidney, liver,heart, skin, small-bowel, and pancreatic-islet-cell transplants, thetopical treatment of inflammatory and hyperproliferative skin diseasesand cutaneous manifestations of immunologically-mediated illnesses (suchas: psoriasis, atopical dermatitis, contact dermatitis and furthereczematous dermatitises, seborrhoeic dermatitis, Lichen planus,Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria,angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupuserythematosus or Alopecia areata), reversible obstructive airwaysdisease, particularly asthma, alopecia, inflammation of mucosa and bloodvessels, cytomegalovirus infection, multidrug resistance, idiopathicthrombocytopenic purpura, and/or hepatic injury associated withischemia.

More particularly, this invention relates to compounds of the generalstructural Formula I: ##STR2## wherein R¹, R², R³, R⁴, R⁵, W and n arehereinafter defined.

This invention also relates to pharmaceutical compositions containingthe compounds, and to a method of use of the present compounds and otheragents for the treatment and prevention of certain afflictions, diseasesand illnesses.

BRIEF DESCRIPTION OF DISCLOSURES IN THE ART

Fujisawa United States, European and Japanese patents and applications(U.S. Pat. No. 4,894,366, issued Jan. 16, 1990, EPO Publication No.0,184,162 and PBJ Disclosure 63-17884) and publications (J. Am. Chem.Soc., 1987, 109, 5031 and J. Antibiotics 1987, 40, 1249, disclose17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (FR-900506) (FK-506) (L-679,934),17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone (FR-900520) and related compoundswhich are the starting materials for the preparation of the compoundsdescribed. The synthetic preparation of the aforementioned startingmaterial (FR-900506) has been reported (J. Am. Chem. Soc., 1989, 111,1157). A Sandoz U.S. patent (U.S. Pat. No. 5,011,844) and Europeanpatent application (EPO Publication No. 0,356,399) disclosestereoisomers of FR-900506 and derivatives at the 17-position. FisonsEuropean and WIPO patent applications (EPO Publication No. 0,323,042 andPCT Publication No. WO89/05304) disclose various derivatives ofFR-900506, FR-900520 and related compounds. A Sandoz European patentapplication (EPO Publication No. 0,437,680) discloses chloro, bromo,iodo and azido derivatives of FR-900506, FR-900520 and relatedcompounds. A Merck European patent application (EPO Publication No.0,428,365) discloses various amino derivatives of FR-900506, FR-900520and related compounds. A Fujisawa UK patent application (UK PublicationNo. GB 2,245,891A) discloses various aryl(lower alkyl) and heteroarylderivatives of FR-900506, FR-900520 and related compounds.

Fujisawa United States patents (U.S. Pat. No. 4,929,611, issued May 29,1990 and U.S. Pat. No. 4,956,352, issued Sep. 11, 1990) disclose the useof FK-506-type compounds in treating resistance to transplantation. ASandoz European patent application (EPO Publication No. 0,315,978)discloses the use of FR-900506 and related compounds in the topicaltreatment of inflammatory and hyperproliferative skin diseases and ofcutaneous manifestations of immunologically-mediated illness. A FisonsWorld patent application (PCT Publication WO 90/14826) discloses the useof FR-900506 and related compounds in the treatment of reversibleobstructive airways disease, particularly asthma. A Fujisawa Europeanpatent application (EPO Publication No. 0,423,714) discloses the use ofFK-506 and derivatives as hair revitalizing agents. Various studies havesuggested the efficacy of FK-506 in the treatment of a number ofailments, including rheumatoid arthritis (C. Arita, et al., Clinicalexp. Immunol., 1990, 82, 456-461; N. Inamura, et al., Clin. Immunol.Immunopathol. 1988, 46, 82-90), recent-onset diabetes (N. Murase, etal., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet, 1990, 336,373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmul. Vis. Sci.,1988, 29, 1265-71), hepatic injury associated with ischemia (M. Sakr, etal., Life Sci., 1990, 47, 687-91) allergic encephalomyelitis (K,Deguchi, et al., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J.McCauley, et al., Lancet, 1990, 335, 674), systemic lupus erythematosus(K. Takabayashi, et al., Clin. Immunol. Immunopathol., 1989, 51,110-117), multidrug resistance (M. Naito, et al., Cancer Chemother.Pharmacol., 1992, 29, 195-200), inflammation of mucosa and blood vessels(PCT Publication WO91/17754), cytomegalovirus infection (UK PublicationGB 2,247,620A), and idiopathic thrombocytophenic purpura and Basedow'sdisease (PCT Publication WO 91/19495).

BACKGROUND OF THE INVENTION

Immunoregulatory abnormalities have been shown to exist in a widevariety of "autoimmune" and chronic inflammatory diseases, includingsystemic lupus erythematosis, chronic rheumatoid arthritis, type 1diabetes mellitus, inflammatory bowel disease, biliary cirrhosis,uveitis, multiple sclerosis and other disorders such as Chron's disease,ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,ichthyosis, and Graves ophthalmopathy. Although the underlyingpathogenesis of each of these conditions may be quite different, theyhave in common the appearance of a variety of autoantibodies andself-reactive lymphocytes. Such self-reactivity may be due, in part, toa loss of the homeostatic controls under which the normal immune systemoperates.

Similarly, following a bone-marrow or an organ transplantation, the hostlymphocytes recognize the foreign tissue antigens and begin to produceantibodies which lead to graft rejection.

One end result of an autoimmune or a rejection process is tissuedestruction caused by inflammatory cells and the mediators they release.Antiinflammatory agents such as NSAID's and corticosteroids actprincipally by blocking the effect or secretion of these mediators butdo nothing to modify the immunologic basis of the disease. On the otherhand, cytotoxic agents such as cyclophosphamide, act in such anonspecific fashion that both the normal and autoimmune responses areshut off. Indeed, patients treated with such nonspecificimmunosuppressive agents are as likely to succumb from infection as theyare from their autoimmune disease.

Cyclosporin A which was approved by the U.S. FDA in 1983 is currentlythe leading drug used to prevent rejection of transplanted organs. Thedrug acts by inhibiting the body's immune system from mobilizing itsvast arsenal of natural protecting agents to reject the transplant'sforeign protein. Though cyclosporin A is effective in fightingtransplant rejection, it is nephrotoxic and is known to cause severalundesirable side effects including kidney failure, abnormal liverfunction and gastrointestinal discomfort.

Newer, safer drugs exhibiting less side effects are constantly beingsearched for in the field.

The 23-membered tricyclo-macrolide immunosuppressant, FR-900506,##STR3##(17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone) and related compounds which wereisolated and characterized by Tanaka, Kuroda, and co-workers at FujisawaPharmaceutical Co. in Japan, see J. Am. Chem. Soc., 1987, 109, 5031, andU.S. Pat. No. 4,894,366, issued Jan. 16, 1990) have been shown topossess exceptional immunosuppressive activity. Fujisawa United Statespatents (U.S. Pat. No. 4,929,611, issued May 29, 1990 and U.S. Pat. No.4,956,352, issued Sep. 11, 1990) disclose the use of FK-506-typecompounds in treating resistance to transplantation. In particular, thecompound FR-900506 has been reported to be 100 times more effective thancyclosporin in the suppression of in vitro immune systems (J.Antibiotics 1987, 40, 1256). In addition, these compounds are reputed topossess topical activity in the treatment of inflammatory andhyperproliferative skin diseases and cutaneous manifestations ofimmunologically-mediated illnesses (EPO Pub. No. 0,315,978).

The compound FK-506 and related compounds further have been suggested tobe useful in the treatment of obstructive airways disease, particularlyasthma (PCT Publication WO 90/14826), rheumatoid arthitis (C. Arita, etal., Clinical exp. Immunol., 1990, 82, 456-461; N. Inamura, et al.,Clin. Immunol. Immunopathol. 1988, 46, 82-90), recent-onset diabetes (N.Murase, et al., Diabetes, 1990, 39, 1584-86; N. Murase, et al. Lancet,1990, 336, 373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmol.Vis. Sci., 1988, 29, 1265-71), hepatic injury associated with ischemia(M. Sakr, et al., Life Sci., 1990, 47, 687-91) allergicencephalomyelitis (K, Deguchi, et al., Brain Nerve, 1990, 42, 391-97),glomerulonephritis (J. McCauley, et al., Lancet, 1990, 335, 674),systemic lupus erythematosus (K. Takabayashi, et al., Clin. Immunol.Immunopathol., 1989, 51, 110-117), multidrug resistance (M. Naito, etal., Cancer Chemother. Pharmacol., 1992, 29, 195-200), inflammation ofmucosa and blood vessels (PCT Publication WO 92/17754), cytomegalovirusinfection (UK Publication GB 2,247,620A), and idiopathicthrombocytophenic purpura and Basedow's disease (PCT Publication WO91/19495).

DETAILED DESCRIPTION OF THE INVENTION

A. Scope of the Invention

The novel compound of this invention has structural Formula I: ##STR4##or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areindependently selected from:

(1) hydrogen;

(2) phenyl;

(3) substituted phenyl in which the substituents are X, Y and Z;

(4) 1- or 2- naphthyl;

(5) substituted 1- or 2- naphthyl in which the substituents are X, Y andZ;

(6) biphenyl;

(7) substituted biphenyl in which the substituents are X, Y and Z;

(8) C₁₋₁₀ alkyl;

(9) substituted C₁₋₁₀ alkyl in which one or more substituent(s) is(are)selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ -alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from

(i) hydrogen,

(ii) C₁₋₁₀ alkyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iii) C₃₋₁₀ alkenyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iv) or where R⁶ and R⁷ and the N to which they are attached can form anunsubstituted or substituted 3-7-membered saturated heterocyclic ringwhich can include one or two additional heteroatoms independentlyselected from the group consisting of O, S(O)_(p), NR¹⁴, wherein R¹⁴ ishydrogen or C₁₋₆ alkyl unsubstituted or substituted by phenyl, and p is0, 1 or 2, the ring being selected from the group consisting of:aziridine, morpholine, thiomorpholine, thiomorpholine-oxide,thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,

(h) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ is as defined above,

(i) --NR⁶ CO₂ --C₁₋₆ alkyl-R⁷,

(j) --NR⁶ CONR⁶ R⁷,

(k) --OCONR⁶ R⁷,

(l) ----COOR⁶,

(m) --CHO,

(n) phenyl,

(o) substituted phenyl in which the substituents are X, Y and Z,

(p) phenyloxy,

(q) substituted phenyloxy in which the substituents are X, Y and Z,

(r) 1- or 2- naphthyl,

(s) substituted 1- or 2- napththyl in which the substituents are X, Yand Z,

(t) biphenyl

(u) substituted biphenyl in which the substituents are X, Y and Z;

(v) --OR¹¹, and

(w) --S(O)_(p) --C₁₋₆ alkyl;

(10) C₃₋₁₀ alkenyl;

(11) substituted C₃₋₁₀ alkenyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z,

(q) --OR¹¹, and

(r) --S(O)_(p) --C₁₋₆ alkyl;

(12) C₃₋₁₀ alkynyl;

(13) substituted C₃₋₁₀ alkynyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y, and Z, and

(q) --OR¹¹ ;

with the proviso that R¹ and R² are not simultaneously hydrogen, methylor combinations thereof;

R³ is hydrogen, hydroxy, --OR¹¹ or C₁₋₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl;

R¹¹ is selected from:

(a) --PO(OH)O⁻ M⁺, wherein M⁺ is a positively charged inorganic ororganic counterion,

(b) --SO₃ ⁻ M⁺,

(c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and

(d) --CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above andthe alkyl is unsubstituted or substituted with one or more substituentsselected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:

(a') hydrogen, and

(b') C₁₋₆ alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined above,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C₁₋₆ alkyl;

W is O or (H, OH);

X, Y and Z independently are selected from:

(a) hydrogen,

(b) C₁₋₇ alkyl,

(c) C₂₋₆ alkenyl,

(d) halogen,

(e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, and mis 0 to 2,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(j) --SOR⁸, wherein R⁸ is as defined above,

(k) --SO₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_(m) -- wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or takentogether form an ethyl or propyl bridge,

(o) ##STR5## wherein R⁹ and m are as defined above, and (p) ##STR6##wherein R⁹ and m are as defined above, and (q) --OR¹¹ ;

or any two of adjacent X, y and Z can be joined to form a ring having 5,6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, theremaining ring atoms being carbon, selected from the group consistingof: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and

n is 1 or 2.

The compounds of the present invention have asymmetric centers and thisinvention includes all of the optical isomers and mixtures thereof.

In addition compounds with carbon-carbon double bonds may occur in Z-and E- forms with all isomeric forms of the compounds being included inthe present invention.

When any variable (e.g., alkyl, aryl, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, etc.)occurs more than one time in any variable or in Formula I, itsdefinition on each occurrence is independent of its definition at everyother occurrence.

As used herein, the term "alkyl" includes those alkyl groups of adesignated number of carbon atoms of either a straight, branched, orcyclic configuration. Examples of "alkyl" include methyl, ethyl, propyl,isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, heptyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, and the like. "Alkoxyl" represents an alkyl group ofindicated number of carbon atoms attached through an oxygen bridge, suchas methoxy, ethoxy, propoxy, butoxy and pentoxy.

"Alkanoyl" is intended to include those alkylcarbonyl groups ofspecified number of carbon atoms, which are exemplified by formyl,acetyl, propanoyl and butyryl; "alkanoyloxy" is intended to includethose alkylcarbonyl groups of specified number of carbon atoms attachedthrough an oxygen bridge, which are exemplified by formyloxy, acetoxy,propionoyloxy, and butyryloxy. "Alkenyl" is intended to includehydrocarbon chains of a specified number of carbon atoms of either astraight- or branched -configuration and at least one unsaturation,which may occur at any point along the chain, such as ethenyl, propenyl,butenyl, pentenyl, dimethyl pentenyl, and the like, and includes E and Zforms, where applicable; and "arylalkyl" represents aryl groups asherein defined which are attached through a straight or branched chainalkyl group of from one to six carbon atoms, such as, for example,benzyl, phenethyl, 3,3-diphenylpropyl, and the like. "Halogen", as usedherein, means fluoro, chloro, bromo and iodo.

As will be understood by those skilled in the art, pharmaceuticallyacceptable salts include, but are not limited to salts with inorganicacids such as hydrochloride, sulfate, phosphate, diphosphate,hydrobromide, and nitrate or slats with an organic acid such as malate,maleate, fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate or palmoate, salicylate andstearate. Similarly pharmaceutically acceptable cations include, but arenot limited to sodium, potassium, calcium, aluminum, lithium andammonium (especially ammonium salts with amines of the formula HNR⁶ R⁷).

One embodiment of the present invention encompasses the compounds ofFormula I wherein: R¹ and R² are independently selected from:

(1) hydrogen;

(2) methyl;

(3) phenyl;

(4) substituted phenyl in which the substituents are X, Y and Z;

(5) 1- or 2-naphthyl;

(6) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ;

(7) biphenyl; and

(8) substituted and biphenyl in which the substituents are X, Y and Z;

with the proviso that R¹ and R² are not simultaneously hydrogen, methylor combinations thereof;

R³ is hydrogen, hydroxy, or C₁₋₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl;

R¹¹ is selected from:

(a) --PO(OH)O⁻ M⁺, wherein M⁺ is a positively charged inorganic ororganic counterion,

(b) --SO₃ ⁻ M⁺,

(c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and

(d) --CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined below andthe alkyl is unsubstituted or substituted with one or more substituentsselected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:

(a') hydrogen, and

(b') C₁₋₆ alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined below,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C₁₋₆ alkyl;

W is O or (H, OH);

X, Y and Z are independently, selected from:

(a) hydrogen,

(b) C₁₋₇ alkyl,

(c) C₂₋₆ alkenyl,

(d) halogen,

(e) --(CH₂)_(m) -NR⁶ R⁷, wherein R⁶ and R⁷ are, independently selectedfrom

(i) hydrogen, or

(ii) C₁₋₆ alkyl unsubstituted or substituted with phenyl, and m is 0 to2,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(j) --SOR⁸, wherein R⁸ is as defined above,

(k) --SO₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_(m) - wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or takentogether form an ethyl or propyl bridge,

(o) ##STR7## wherein R⁹ and m are as defined above, and (p) ##STR8##wherein R⁹ and m are as defined above, and (q) --OR¹¹ ;

or any two of adjacent X, Y and Z can be joined to form a ring having 5,6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, theremaining ring atoms being carbon, selected from the group consistingof: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and

n is 1 or 2.

Another embodiment of the present invention encompasses the compounds ofFormula I wherein:

R¹ and R² are independently selected from:

(1) hydrogen;

(2) C₁₋₁₀ alkyl;

(3) substituted C₁₋₁₀ alkyl in which one or more substituent(s) is (are)selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ -alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from

(i) hydrogen,

(ii) C₁₋₁₀ alkyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iii) C₃₋₁₀ alkenyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iv) or where R⁶ and R⁷ and the N to which they are attached can form anunsubstituted or substituted 3-7-membered saturated heterocyclic ringwhich can include one or two additional heteroatoms independentlyselected from the group consisting of O, S(O)_(p), NR¹⁴, wherein R¹⁴ ishydrogen or C₁₋₆ alkyl unsubstituted or substituted by phenyl, and p is0, 1 or 2, the ring being selected from the group consisting of:aziridine, morpholine, thiomorpholine, thiomorpholine-oxide,thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,

(h) --NR⁶ CO--C₁₋₆ alkyl--R⁷, wherein R⁶ is as defined above,

(i) --NR⁶ CO₂ --C₁₋₆ alkyl--R⁷,

(j) --NR⁶ CONR⁶ R⁷,

(k) --OCONR⁶ R⁷,

(l) --COOR⁶,

(m) --CHO,

(n) phenyl,

(o) substituted phenyl in which the substituents are X, Y and Z,

(p) phenyloxy,

(q) substituted phenyloxy in which the substituents are X, Y and Z,

(r) 1- or 2-naphthyl,

(s) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(t) biphenyl

(u) substituted biphenyl in which the substituents are X, Y and Z;

(v) --OR¹¹, and

(w) --S(O)_(p) --C₁₋₆ alkyl;

(4) C₃₋₁₀ alkenyl;

(5) substituted C₃₋₁₀ alkenyl in which one or more substituent(s) is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z,

(q) --OR¹¹, and

(r) --S(O)_(p) --C₁₋₆ alkyl;

(6) C₃₋₁₀ alkynyl;

(7) substituted C₃₋₁₀ alkynyl in which one or more substituent(s) is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z, and

(q) --OR¹¹ ;

with the proviso that R¹ and R² are not simultaneously hydrogen, methylor combinations thereof;

R³ is hydrogen, hydroxy, --OR¹¹ or C₁₋₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl;

R¹¹ is selected from:

(a) --PO(OH)O⁻ M⁺, wherein M⁺ is a positively charged inorganic ororganic counterion,

(b) --SO₃ ⁻ M⁺,

(c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and

(d) --CO--C₁₋₆ alkyl--NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above andthe alkyl is unsubstituted or substituted with one or more substituentsselected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:

(a') hydrogen, and

(b') C₁₋₆ alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined above,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C₁₋₆ alkyl;

W is O or (H, OH);

X, Y and Z independently are selected from:

(a) hydrogen,

(b) C₁₋₇ alkyl,

(c) C₂₋₆ alkenyl,

(d) halogen,

(e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, and mis 0 to 2,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(j) --SOR⁸, wherein R⁸ is defined above,

(k) --SO₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_(m) - wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or takentogether form an ethyl or propyl bridge,

(o) ##STR9## wherein R⁹ and m are as defined above, and (p) ##STR10##wherein R⁹ and m are as defined above, and (q) --OR¹¹ ;

or any two of adjacent X, Y and Z can be joined to form a ring having 5,6 or 7 atoms, said ring atoms comprising 1 or 2 oxygen atoms, theremaining ring atoms being carbon, selected from the group consistingof: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and

n is 1 or 2.

In the present invention it is preferred that in compounds of Formula I:

R¹ and R² are independently selected from:

(1) hydrogen;

(2) phenyl;

(3) substituted phenyl in which the substituents are X, Y and Z;

(4) 1- or 2-naphthyl;

(5) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ;

(6) C₁₋₁₀ alkyl;

(7) substituted C₁₋₁₀ alkyl in which one or more substituent(s) is (are)selected from

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ -alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl--C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from

(i) hydrogen,

(ii) C₁₋₁₀ alkyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iii) C₃₋₁₀ alkenyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e'--CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iv)or where R⁶ and R⁷ and the N to which they are attached may form anunsubstituted or substituted 3-7-membered saturated heterocyclic ringwhich may

include one or two additional heteroatoms independently selected fromthe group consisting of O, S(O)_(p), NR¹⁴, wherein R¹⁴ is hydrogen orC₁₋₆ alkyl unsubstituted or substituted by phenyl, and p is 0, 1 or 2,the ring being selected from the group consisting of: aziridine,morpholine, thiomorpholine, thiomorpholine-oxide,thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,

(h) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ is as defined above,

(i) --NR⁶ CO₂ --C₁₋₆ alkyl-R⁷,

(j) --NR⁶ CONR⁶ R⁷,

(k) --OCONR⁶ R⁷,

(l( --COOR⁶,

(m) --CHO,

(n) phenyl,

(o) substituted phenyl in which the substituents are X, Y and Z,

(p) phenyloxy,

(q) substituted phenyloxy in which the substituents are X, Y and Z,

(r) 1- or 2- naphthyl,

(s) substituted 1- or 2- and naphthyl in which the substituents are X, Yand Z, and

(t) --OR¹¹ ;

(8) C₃₋₁₀ alkenyl;

(9) subsituted C₃₋₁₀ alkenyl in which one or more substituent(s) is(are)selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) --OCOC₁₋₆ alkyl,

(e) C₂₋₈ alkenyl,

(f) phenyl,

(g) substituted phenyl in which the substituents are X, Y and Z,

(h) 1- or 2- naphthyl, and

(i) substituted 1- or 2- naphthyl in which the substituents are X, Y andZ,

(10) C₃₋₁₀ alkynyl;

(11) substituted C₃₋₁₀ alkynyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) --OCOC₁₋₆ alkyl,

(e) phenyl,

(f) substituted phenyl in which the substituents are X, Y and Z,

(g) 1- or 2- naphthyl, and

(h) substitued 1- or 2- naphthyl in which the subsitutens are X, Y andZ;

with the proviso that R¹ and R² are not simultaneosuly hydrogen, methylor combinations thereof;

R³ is hydrogen, or hydroxy;

R⁴ is hydrogen;

R⁵ is ethyl, propyl or allyl;

R¹¹ is selected from:

(a) --PO(OH)O⁻ M³⁰, wherein M⁺ is a positively charged inorganic ororganic ounterion,

(b) --SO₃ ⁻ M⁺,

(c) --CO(CH₂)_(q) CO₂ ⁻ M³⁰, wherein q is 1-3, and

(d) --CO--C₁₋₆ alkyl--NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above andthe alkyl is unsubstituted or substituted with one or more substitutentsselected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:

(a') hydrogen, and

(b') C₁₋₆ alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined above,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C₁₋₆ alkyl;

W is O or (H, OH);

X. Y and Z independently are selected from:

(a) hydrogen,

(b) C₁₋₇ alkyl,

(c) C₂₋₆ alkenyl,

(d) halogen,

(e) --CN,

(f) --CHO,

(g) --CF₃,

(h) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(i) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(j) R⁹ O(CH₂)_(m) - wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(k) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or takentogether form an ethyl or propyl bridge,

(l) ##STR11## wherein R⁹ and m are as defined above, (m) ##STR12##wherein R⁹ and m are as defined above, and; (n) --OR¹¹ ;

or any two of adjacent X, Y and Z may be joined to form a ring having 5,6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, theremaining ring atoms being carbon, selected from the group consistingof: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dixoanyl; and

n is 2;

and pharmaceutically acceptable salts thereof.

Representative compounds of the present invention include the compoundsidentified as follows:

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-phenyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-phenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-phenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-chlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-methylphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,-25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-phenoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-phenoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-phenoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,-25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-1-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(naphth-1-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-1-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-)naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(napth-2-yloxy)-4"-hydrocyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-methoxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,k27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-methoxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-methoxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,15-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(3'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dichlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(phenanthr-9-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-methylenedioxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl[-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'",3'"-dihydrobenzofuran-5-yloxy)-3"-methoxycyclohexyl)-1'-methylvinly]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'",4'"-benzodioxane-6-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,2,14-trihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-3,10,16-trione;

17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-dimethylamino)-phenyloxy-3"-hydrocycyclohexyl)-1'-methylvinly]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-dimethylamino)phenyloxcyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]-octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-butynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-allyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-allyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-iropropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinly]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-sec-butenyloxy-3"-hydrocyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(trans-2'"-butenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]ocacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(trans-2'"-butenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinly]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo]22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18- ene-2,3,10,16-tetraone;

17-Ethyl-1,14-hydroxy-12-[2'-(3"-cinnamyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-sec-butenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinly]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'4"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylthiophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-methylphenyloxy)-3"-methoxycyclohexyl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dimethylphenyloxy)-3"-methoxycyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-butynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-cinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-allyoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3"-allyloxy-4"hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3"-hydroxy-4"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-trans-2'"-butynyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3"-(trans-2'"-butenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3"-hydroxy-4"-(3'"methyl-2-butenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3'"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3"-hydroxy-4"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3"-cinnamyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-sec-phenethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-methylcinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methyl-2'",-4"'-hexadienyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-methoxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-methylene-dioxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'",4'"-dimethyl-2'"-trans-pentenyloxy)-3"methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'(4"-(3'"cyclohexyl2'"-trans-propenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-p-chlorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-p-bromocinnamyloxy-3"methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-p-fluorophenylpropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(3",4"-diallyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0.sup.4,9]octacos-18-ene-2,3,10,16-tetraone;

17Ethyl-1-hydroxy-12-[2'-(3",4"-dipropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0.sup.4,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-benzylamino)-ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-benzyloxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17Ethyl-1,14-dihydroxy-12-[2'-(4"-(napth-2-yloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(ethoxycarbomethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"(2'"-(3'"-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(4""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'(4"-(2'"-(4""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(4""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"(2'"-(3"",5""-difluorophenyl)-2'"-oxo-ethyloxy)-3"methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-(3"",5""-didifluorophenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3"",5""-difluorophenyl)-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-oxo-ethyloxy)3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3"",5""-difluorophenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-(3"",5""-difluorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3"",5""-difluorophenyl)-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-fluorocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",5'"-difluorocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-nitrocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-phenyl-2'"-propynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-propenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-hydroxyphenpropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxymethylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxycinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",5'"-difluorocinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carbomethoxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-isopropylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-butylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-acetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(N-phenylacetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(N-benzylacetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-carboxymethyoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(N-benzylamidoxymethyoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(N-methyltyrosine)amidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(m-methylphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(p-methylphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(m-methylphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(m-ethylphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenylethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-acetoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-morpholinoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-ylmethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'",5'"-methylenedioxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-N,N,-dimethylaminophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-(2""-dioxolanylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-formylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-carboxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dimethoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-trifluoromethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",5'"-bis-(trifluoromethyl)phenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-methylphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-hydroxyphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-hydroxymethylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-hydroxymethylphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-formylphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-N,N-dimethylaminophenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-N,N-dimethylaminophenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-phenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-phenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and;

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-methoxyphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone; and

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(3'"-methoxyphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

B. Preparation of Compounds Within the Scope of the Present Invention

The starting materials for the preparation of the compounds of thisinvention are represented by Formula II: ##STR13## wherein: Q ishydrogen or methyl;

W is O or (H, OH);

R³ is hydrogen, hydroxy, or C₁ -C₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl; and

n is 1 or 2.

The production and characterization of compounds of Formula II is wellknown in the literature (see U.S. Pat. No. 4,894,366 issued Jan. 16,1990; U.S. Pat. No. 4,929,611 issued May 29, 1990; U.S. Pat. No.3,244,592 issued Apr. 15, 1966; EPO Publication No. 0,323,042; EPOPublication No. 0,356,399; PBJ Disclosure 63-17884; J. Am. Chem. Soc.,1987, 109, 5031; and J. Antibiotics, 1987, 40, 1249). Both biologicalfermentatioin and synthetic processes may be found. A synthetic route tocompounds of Formula II can involve modifications of a route describedin J. Am. Chem. Soc. 1989, 111, 1157.

Biological fermentation followed by synthetic modification is presentlyfavored in the art as the method to produce compounds of Formula II.Organisms belonging to the genus Streptomyces such as Streptomycestsukubaensis, No. 9993 and Streptomyces hygroscopicus, No. 7238 placedin an aqueous nutrient medium will produce desired compounds in isolableamounts. The nutrient medium contains sources of assimilable carbon andnitrogen, preferably under aerobic conditions. Produced in fermentationare four compounds of Formula II, (A) where Q is methyl, W is O, R³ ishydroxyl, R⁴ is hydrogen, R⁵ is allyl and n is 2; (B) where Q is methyl,W is O, R³ is hydroxyl, R⁴ is hydrogen, R⁵ is ethyl and n is 2; (C)where Q is methyl, W is O, R³ is hydroxyl, R⁴ is hydrogen, R⁵ is methyland n is 2; and (D) where Q is methyl W is O, R³ is hydroxyl, R⁴ ishydrogen, R⁵ is allyl and n is 1.

A lyophilized sample of the isolated Streptomyces tsukubaensis, No. 9993was deposited with the Fermentation Research Institute, Agency ofIndustrial Science and Technology (No. 1-3, Higashi 1-chome, YatabemachiTsukuba-gun, Ibaraki Prefecture, Japan) under the deposit number of FERMP-7886 (deposit date: Oct. 5th, 1984), and then converted to BudapestTreaty route of the same depository on Oct. 19, 1985 under the newdeposit number of FERM BP-927.

Using the four compounds produced in fermentation above, the remainingcompounds of Formula II may be easily produced. The allyl of R⁵ may beconveniently reduced to propyl by well known methods, for example asdescribed in U.S. Pat. No. 4,894,366. The hydroxy of R³ may be protectedby well known methods, for example as disclosed in EPO Publication No.0,323,042. Likewise, the hydroxy at C-4" may also be protected. Inaddition, the hydroxy of R³ may be reduced to a hydrogen or eliminatedto form a double bond with R⁴ (by methods disclosed in U.S. Pat. No.4,894,366 or EPO Publication No. 0,323,042 or EPO Publication No.0,413,532). The carbonyl of W may be reduced to the alcohol by methodsdisclosed in EPO Publication No. 0,323,042 or by methods disclosed inU.S. Pat. No. 5,064,835 or in EPO Publication No. 0,445,975.

The methyl of Q as produced may be replaced with hydrogen ordemethylated and subsequently protected as desired, if necessary. Thisdemethylation of compounds wherein Q is methyl may be carried out in afermentation reaction using the compounds of Formula II as a feedstock.For instance, compound A named under Formula II above may bedemethylated at Q above by using the microorganism Actinomycetales ATCCNo. 53771 (described in U.S. Pat. No. 4,981,792, issued Jan. 1, 1991) orby using the microorganism Streptomyces tsukubaensis, No. 9993(described in EPO Publication No. 0,353,678). Similarly, compound Bnamed under Formula II above may be demethylated at Q above using themicroorganism Actinoplanacete sp. ATCC No. 53771 (described in EPOPublication No. 0,349,061). In addition the compound of Formula IIwherein Q is H, W is O, R³ is hydroxy, R⁴ is hydrogen, R⁵ is ethyl and nis 2 may be produced directly by fermentation using the mutantmicroorganism Streptomyces hygroscopicus sup. ascomyceticus, No. 53855(being a blocked mutant of Streptomyces hygroscopicus sup.ascomyceticus, No. 14891) (as described in EPO Publication 0,388,152).Similarly, the compound of Formula II wherein Q is hydrogen, W is O, R³is hydroxy, R⁴ is hydrogen, R⁵ is methyl and n is 2 may be produceddirectly by fermentation using the mutant microorganism Streptomyceshygroscopicus sup. ascomyceticus, No. 53855 (being a blocked mutant ofStreptomyces hygroscopicus sup. ascomyceticus, No. 14891) (as describedin EPO Publication 0,388,153). Also, the compound of Formula II whereinQ is hydrogen, R³ is hydroxy, R⁴ is hydrogen, R⁵ is allyl, W is 0 and nis 2 and the compound of Formula II wherein the C-3" position is oxo(keto), R³ is hydroxy, R⁴ is hydrogen, R⁵ is allyl, W is O and n is 2may be produced directly by fermentation using the microorganismStreptomyces tsukubaensis, No. 9993 (described in EPO Publication No.0,353,678). The hydroxy of C-3" may be protected by methods similar tothose known for the protection of the hydroxyl groups of R³ and/or C-4",for example as disclosed in U.S. Pat. No. 4,894,366.

Suitable protecting groups for hydroxyl include those groups well knownin the art such as:

1-(lower alkylthio)(lower)alkyl, wherein "lower alkyl" indicates astraight, cyclic or branched chain of one to six carbon atoms, such aslower alkylthiomethyl (e.g. methylthiomethyl, ethylthiomethyl,propylthiomethyl, isopropylthiomethyl, butylthiomethyl,isobutylthiomethyl, hexylthiomethyl, etc.), and the like, in which thepreferred one may be C₁ -C₄ alkylthiomethyl and the most preferred onemay be methylthiomethyl; trisubstituted silyl such astri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, tributysilyl,tri-i-propylsilyl, t-butyldimethylsilyl, tri-i-butylsilyl, etc.), loweralkyldiarylsilyl (e.g. methyl-diphenylsilyl, ethyl-diphenylsilyl,propyl-diphenylsilyl, t-butyldiphenylsilyl, etc.), and the like, inwhich the preferred one may be tri(C₁ -C₄)alkylsilyl and C₁ -C₄alkyl-diphenylsilyl, and the most preferred one may betert-butyl-dimethylsilyl, tri-i-propylsilyl andtert-butyl-diphenylsilyl; acyl such as aliphatic acyl, aromatic acyl andaliphatic acyl substituted with aromatic group, which are derived fromcarboxylic acids; and the like.

Compounds A, B, C and D of Formula II, organisms to produce the same,conditions of fermentation, separation techniques, and chemicalmodification of the products are fully described in U.S. Pat. No.4,894,366, issued Jan. 16, 1990 and U.S. Pat. No. 4,929,611, issued May29, 1990. The novel processes for preparing the novel compounds of thepresent invention are illustrated as follows, wherein R¹, R², R³, R⁵, Q,W and n are as defined above unless otherwise indicated. It will bereadily apparent to one of ordinary skill in the art reviewing thesynthetic route depicted below that other compounds within Formula I canbe synthesized by substitution of appropriate reactants and agents inthe synthesis shown below. ##STR14##

Reaction Scheme A:

As shown in Reaction Scheme A, a solution of a 4"-hydroxy-3"-methoxymacrolide in an inert organic solvent such as methylene chloride,benzene, toluene, chloroform, or the like or mixtures thereof is treatedwith a triarylbismuth diacetate reagent (wherein R¹ is aryl) (preparedimmediately prior to use by the addition of acetic acid to a suspensionof a triarylbismuth carbonate in an inert organic solvent such asmethylene chloride, chloroform or the like or mixture thereof) in thepresence of a catalytic amount of copper(II) acetate at a temperature of20°-50° C., preferably room temperature, for a period of one hour toseven days, preferably one day, to give the 4"-O-aryl-3"-methoxymacrolide. Alternatively, the triarylbismuth(V) reagent can be preparedby treatment of a triarylbismuthine with a suitable oxidant such asperacetic acid, iodobenzene diacetate, bis(trifluoroacetoxy)iodobenzeneand the like in an inert solvent such as methylene chloride, chloroform,benzene, toluene and the like. The triarylbismuth(V) reagent can be usedwithout purification or can be purified by silica gel chromatograhy.Triarylbismuthines may be prepared by the reaction of an appropriatearyl Grignard reagent with bismuth trichloride in an inert organicsolvent such as tetrahydrofuran, diethyl ether, or 1,4-dioxane, ormixtures thereof, at or near room temperature for a period of 1 to 48hours. General procedures for the preparation and use of triaryl bismuthreagents may be found in Barton, D. H. E., et al., J. Chem. Soc. Chem.Commun., 1986, 65 and references cited therein.

Reaction Scheme B:

Similarly, as shown in Reaction Scheme B, a solution of the3",4"-dihydroxy macrolide is treated with a triarylbismuth diacetatereagent as described in Reaction Scheme A, to give a mixture of the3"-hydroxy-4"-O-aryl macrolide, the 3"-O-aryl-4"-hydroxy macrolide, andthe 3",4"-di-O-aryl macrolide. At this stage, a solution of3"-hydroxy-4"-O-aryl macrolide, or 3"-O-aryl-4"-hydroxy macrolide can betreated with a different triarylbismuth diacetate reagent (preparedimmediately prior to use by procedures analogous to those disclosedabove), to give 3"-O-aryl-4"-O-aryl macrolides.

Reaction Scheme C:

As shown in Reaction Scheme C. the 14-hydroxy group of a macrolide(wherein R¹, R², R⁵, W and n are as defined above) may be eliminated bytreatment with p-toluenesulfonic acid, benzenesulfonic acid,methanesulfonic acid, p-nitrobenzenesulfonic acid,p-bromobenzenesulfonic acid, p-chlorobenzenesulfonic acid, orp-methoxybenzenesulfonic acid, or mixtures thereof, in an inert organicsolvent such as benzene, or toluene or the like at a temperature of 40°C. to solvent reflex temperature, preferably 60° C., for about 0.5 to 6hours, or a sufficient period of time to eliminate the 14-hydroxy group.Neutralization with an aqueous solution of a weak base such as aqueoussaturated sodium bicarbonate gives the 14,15-dehydro macrolide. The14-hydroxy group may also be eliminated by activation followed by basicelimination, as described in U.S. Pat. No. 4,894,366.

Reaction Scheme D:

As shown in Reaction Scheme D the macrolide (wherein R¹ _(a) and/or R²_(a) is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl andwherein R³ _(a) is hydroxy or C₁₋₆ alkoxy, R⁴ _(a) is hydrogen, or R³_(a) and R⁴ _(a) taken together form a double bond) is reduced under anatmosphere of hydrogen in the presence of a nobel metal catalyst, suchas rhodium on carbon catalyst or rhodium on alumina catalyst, at apressure of atmospheric pressure to 40 psig, at or near room temperaturein an organic solvent such as ethyl acetate or ethanol for about 1 to 24hours, or until the requisite amount of hydrogen is absorbed to reducethe olefin and give the reduced macrolide.

By changing the sequence of synthetic steps, all possible variations ofsubstitution can be achieved. For example, the C-14 hydroxy group may beelminated and the resultant double bond reduced prior to theintroduction of alkenyl or alkynyl substituents at C-3" and/or C-4".

Reaction Scheme E:

As shown in Reaction Scheme E, a solution of the 4"-hydroxy 3"-methoxymacrolide in an inert organic solvent such as methylene chloride,chloroform, pentane, hexane, cyclohexane, heptane or the like ormixtures thereof is treated with an alkyl, alkenyl or alkynyltrichloroacetimidate reagent (prepared by the reaction of an appropriatesodium alkoxide with trichloroacetonitrile, such as described by Wessel,H. P., Iversen, T., Bundle, D. R., J. Chem. Soc., Perkin Trans. I, 1985,2247) in the presence of a mild acid catalyst such astrifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonicacid, benzenesulfonic acid, p-nitrobenzenesulfonic acid,p-bromobenzenesulfonic acid, p-chlorobenzenesulfonic acid, orp-methoxybenzenesulfonic acid, or mixtures thereof at a temperature of20°-50° C. preferably room temperature, for a period of one hour toseven days, preferably one day, to give the 4"-O-alkyl, -alkenyl or-alkynyl 3"-methoxy macrolide.

Reaction Scheme E2:

Alternatively, as shown in Reaction Scheme E2, ketone derivatives can beprepared by direct alkylation of the macrolide by treatment with anunsubstituted or substituted 2-bromoacetophenone in an inert solventsuch as N,N-dimethylformamide or tetrahydrofuran and a fluoride sourcesuch as potassium fluoride or cesium fluoride at 25°-70° C. for a periodof 24-72 hours.

Reaction Scheme F:

Similarly, as shown in Reaction Scheme F, (wherein R=R¹ =R²) a solutionof the 3",4"-dihydroxy macrolide in an inert organic solvent such asmethylene chloride, chloroform, pentane, hexane, cyclohexane, heptane orthe like or mixtures thereof is treated with an alkyl, alkenyl, oralkynyl trichloroacetimidate (prepared by the reaction of an appropriatesodium alkoxide with trichloroacetonitrile, such as described by Wessel,H. P., Inversen, T., Bundle, D. R., J. Chem. Soc., Perkin Trans. I,1985, 2247) in the presence of a mild acid catalyst such astrifluoromethanesulfonic acid, p-toluene-sulfonic acid, methanesulfonicacid, benzenesulfonic acid, p-nitrobenzensulfonic acid,p-bromobenzenesulfonic acid, p-chlorobenzenesulfonic acid, orp-methoxybenzenesulfonic acid, or mixtures thereof of at a temperatureof 20°-50° C., preferably 40° C., for a period of one hour to sevendays, preferably 6 hours, to give a mixture of the 3"-O-alkyl, -alkenylor -alkynyl 4"-hydroxy macrolide, the 3"-hydroxy 4"-O-alkyl, -alkenyl or-alkynyl macrolide and the 3",4"-di-O-alkyl, -alkenyl or -alkynylmacrolide.

Reaction Scheme G:

The procedures described in Reaction Schemes C and D may optionally beconducted following the procedures of Reaction Scheme E or F.Alternatively, the procedures described in Reaction Scheme G may beperformed. In Reaction Scheme G the macrolide (wherein R¹ _(a) and/or R²_(a) is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl andwherein R³ _(a) is hydroxy or C₁₋₆ alkoxy, R⁴ _(a) is hydrogen, or R³_(a) and R⁴ _(a) taken together form a double bond) is reduced withtri-n-butyltin hydride in the presence oftetrakis(triphenylphosphine)palladium(O) catalyst and acetic acid in anorganic solvent such as toluene or tetrahydrofuran at or near roomtemperature for about 2 to 10 hours to give the reduced macrolide.

The procedures described in Reaction Scheme F may be conducted on themono-substituted products of Reaction Scheme B (and visa versa) toobtain the mixed disubstituted compounds. In fact, within ReactionSchemes B and F, treatment of the mono-substituted product with adifferent reagent will afford the mixed disubstituted compounds.

Reaction Scheme H:

Protection of the C-3", C-4" and/or the C-14 hydroxy group may beaccomplished by methods known in the prior art for compounds of FormulaII such as by treatment with: 2,6-lutidine and triisopropylsilyltrifluoromethanesulfonate in a solution of methylene chloride;2,6-lutidine and t-butyldimethylsilyl trifluoromethanesulfonate in asolution of methylene chloride; pyridine and acetic anhydride in asolution of methylene chloride; pyridine and benzoyl chloride in asolution of methylene chloride; pyridine and p-nitrobenzoyl chloride ina solution of methylene chloride; imidazole and t-butyldiphenylsilylchloride in a solution of methylene chloride; and the like. For example,as shown in Reaction Scheme H, the C-4", 14-dihydroxy C-3"-methoxymacrolide (or the C-3", 4", 14-trihydroxy macrolide) may be protected atC-14 as the t-butyldimethylsilyl ether by treatment witht-butyldimethylsilyl trifluoromethanesulfonate in methylene chloride togive the C-4",3"-di-O-TBDMS macrolide (or the C-3",4", 14-tri-O-TBDMSmacrolide). Treatment with toluenesulfonic acid in methanol results inselective removal of the C-4" silyl ether (and C-3" silyl ether, ifpresent) to give the C-14-O-TMBDMS macrolide.

Reaction Scheme I:

As shown in Reaction Scheme I, the 4"-hydroxy-3"-R² O-macrolide oralternatively the 3"-hydroxy-4"-R¹ O-macrolide (not depicted) (whereinR³ is protected hydroxy or hydrogen) may be reacted with an alkenyltrichloroacetimidate (wherein R¹ is C₃₋₁₀ alkenyl) under conditionsdescribed in Reaction Scheme F to give the C-4"-O-alkenyl macrolide.Treatment with a stochiometric amount of osmium tetraoxide in an inertorganic solvent, such as diethyl ether or tetrahydrofuran, in thepresence of an amine base, such as pyridine or 4-methylmorpholineN-oxide, at or near room temperature gives the corresponding glycol(wherein A is C₁₋₈ alkyl). Treatment of the glycol with sodiummetaperiodate in a solution of tetrahydrofuran/water gives the aldehyde.Alternatively, the alkenyl macrolide may be treated with sodiummetaperiodate in the presence of a catalytic amount of osmium tetroxidein an organic solvent to give the aldehyde directly. The aldehyde can befurther oxidized to the carboxylic acid by treatment with sodiumchlorite in buffered, aqueous tert-butanol.

Reaction Scheme J:

A variety of compounds may be prepared from the corresponding aldehydeas illustrated in Reaction Scheme J. The aldehyde may be reacted with aprimary or secondary amine (wherein R⁶ and R⁷ are as defined above) inan organic solvent such as tetrahydrofuran to give an imine which isreduced in situ with a hydride reducing agent, such as potassiumtriphenyl borohydride or sodium cyanoborohydride, to give the macrolidebearing as amino alkoxy functionality at C-4". The aldehyde may also bereduced to the corresponding alcohol by treatment with a hydridereducing agent, such as potassium triphenyl borohydride or sodiumcyanoborohydride in an organic solvent such as tetrahydrofuran. Thealcohol may be further modified by utlizing the methods of ReactionScheme B (wherein R¹ _(a) is unsubstituted or substituted phenyl,naphthyl or biphenyl) or Reaction Scheme F (wherein R¹ _(b) isunsubstituted or substituted alkyl, alkenyl or alkynyl). The proceduresdescribed in Reaction Scheme J are readily applicable to the preparationof compounds bearing analogous functionality at C-3".

Reaction Scheme K:

Amide derivatives may be prepared from the carboxylic acid asillustrated in Reaction Scheme K. The carboxylic acid may be coupledwith a primary or secondary amine, HNR⁶ R⁷ (wherein R⁶ and/or R⁷ are asdefined) by any of the peptide coupling methods commonly used in theart, such as with BOP reagent, DCC/HOBT, or EDC/HOBT.

Reaction Scheme L:

Hydroxy and keto derivatives may be prepared from the correspondingaldehyde as illustrated in Reaction Scheme L. The aldehyde is reactedwith a nucleophilic organometallic reagent such as a Grignard reagent,an organolithium reagent, or an organocerium reagent in an organicsolvent such as methylene chloride or tetrahydrofuran to give thesubstituted hydroxy compound. Removal of hydroxy protecting groups atother positions of the macrolide (if necessary) gives the macrolidebearing a substituted hydroxy alkoxy functionality at C-4". The alcoholmay also be oxidized to the corresponding ketone by well known methods,such as with 4-methylmorpholine-N-oxide in the presence oftetrapropylammonium perruthenate catalyst under dehydrative conditions.Removal of hydroxy protecting groups (if necessary) gives the macrolidebearing a substituted keto alkoxy functionality at C-4". The proceduresdescribed in Reaction Scheme L are readily applicable to the preparationof compounds bearing analogous functionality at C-3".

Reaction Scheme M:

Hydroxy macrolides (wherein R¹, R², and/or R³ bear a hydroxy group) maybe further derivatized by alkylation, acylation or phosphorylation togive ether, ester or phosphate derivatives (wherein R¹, R² and/or R³bear an --OR¹¹ as defined above) by procedures well known to thepractitioner of the art.

The object compounds of Formula I obtained according to the reactions asexplained above can be isolated and purified in a conventional manner,for example, extraction, precipitation, fractional crystallization,recrystallization, chromatography, and the like.

It is to be noted that in the aforementioned reactions and thepost-treatment of the reaction mixture therein, the stereoisomer(s) ofstarting and object compounds due to asymmetric carbon atoms(s) ordouble bond(s) of the object compounds of Formula I may occasionally betransformed into the other stereoisomer(s), and such cases are alsoincluded within the scope of the present invention.

In the present invention, compounds with asymmetric centers may occur asracemates, as diastereomeric mixtures and as individual diastereomers,with all isomeric forms of the compounds being included in the presentinvention. These may be prepared by methods such as those disclosed inpublications which describe synthetic routes to fragments of themacrolide FR-900506 and the total synthesis of the macrolide FR-900506itself (See for example, J. Am. Chem. Soc. 1989, 111, 1157; J. Am. Chem.Soc. 1990, 112, 2998; J. Org. Chem. 1990, 55, 2786; J. Am. Chem. Soc.1990, 112, 5583. Tetrahedron Lett. 1988, 29, 277; Tetrahedron Lett.1988, 29, 281; Tetrahedron Lett. 1988, 29, 2895; J. Org. Chem. 1988, 53,4643; Tetrahedron Lett. 1988, 29, 4245; Tetrahedron Lett. 1988, 29,4481; J. Org. Chem. 1989, 54, 9; J. Org. Chem. 1989, 54, 11; J. Org.Chem. 1989, 54, 12; J. Org. Chem. 1989, 54, 15; J. Org. Chem. 1989, 54,17; Tetrahedron Lett. 1989, 30, 919; Tetrahedron Lett. 1989, 30, 1037;J. Org. Chem. 1989, 54, 2785; J. Org. Chem. 1989, 54, 4267; TetrahedronLett. 1989, 30, 5235; Tetrahedron Lett. 1989, 30, 6611; TetrahedronLett. 1989, 30, 6963; Synlett 1990, 38; J. Org. Chem. 1990, 55, 2284; J.Org. Chem. 1990, 55, 2771; J. Org. Chem. 1990, 55, 2776; TetrahedronLett. 1990, 31, 1439; Tetrahedron Lett. 1990, 31, 1443; TetrahedronLett. 1990, 31, 3007; Tetrahedron Lett. 1990, 31, 3283, 3287).

The compounds of the present invention are capable of forming salts withvarious inorganic and organic acids, and bases and such salts are alsowithin the scope of this invention. Examples of such acid addition salts(which are negative counterions defined herein as M⁻) include acetate,adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate,heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,methanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate,propionate, succinate, tartrate, tosylate, and undecanoate. Base salts(which are positive counterions defined herein as M⁺) include ammoniumsalts, alkali metal salts such as sodium, lithium and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine and so forth. Also, the basic nitrogen-containing groups may bequaternized with such agents as: lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl chlorides, bromidesand iodides; aralkyl halides like benzyl bromide and others. Thenon-toxic physiologically acceptable salts are preferred, although othersalts are also useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

C. Utility of the compounds within the scope of the invention

The compounds of Formula I may be employed as immunosuppressants orantimicrobial compounds by methods and in dosages known in the prior artfor compounds of Formula II. These compounds possess pharmacologicalactivity such as immunosuppressive activity, antimicrobial activity, andthe like, and therefore are useful for the treatment and prevention ofthe resistance to transplantation or transplantation rejection of organsor tissues such as heart, kidney, liver, duodenum, small-bowel, medullaossium, skin, pancreatic islet-cell, etc., graft-versus-host diseases bymedulla ossium transplantation, automimmune diseases such as rheumatoidarthritis, systemic lupus erthematosis, Hashimoto's thyroiditis,multiple sclerois, myasthenia gravis, type I diabetes, uveitis, allergicencephalomyelitis, glomerulonephritis, etc., and infectious diseasescuased by pathogenic microorganisms.

The compounds of Formula I are also useful for treating or preventinginflammatory and hyperproliferative skin diseases and cutaneousmanifestations of immunologically-mediated illnesses such as: psoriasis,atopical dermatitiis, contact dermatitis and further eczematousdermatitises, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullousPemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides,erythemas, acne, cutaneous eosinophilias or Alopecia areata. Moreparticularly, the compounds of Formula I are useful in hairrevitalizing, such as in the treatment or prevention of male patternalopecia or alopecia senilis, by providing epilation prevention, hairgermination, and/or a promotion of hair generation and hair growth.

The compounds of Formula I are further useful for treating or preventingreversible obstructure airways disease, including conditions such asasthma, including bronchial asthma, allergic asthma, intrinsic asthma,extrinsic asthma and dust asthma, particularly chronic or inveterateasthma (for example late asthma and airway hper-responsiveness),bronchitis and the like. The compounds of Formula I may also be usefulfor treating hepatic injury associated with ischemia.

The compounds of Formula I are also useful for treating multidrugresistance of tumor cells, (i.e. enhancing the activity and/orsensitivity of chmmoterapeutic agents), preventing or treatinginflammation of mucosa or blood vessels, LTB₄ -mediated diseases,gastric ulcers, vascular damage cuased by ischemic diseases andthrombosis, ischemic bowel disease, inflammatory bowel disease (e.g.,Crohn's disease and ulcerative colitis) necrotizing enterocolitis, orintestinal lesions associated with thermal burns, cytomegalovirusinfection, particularly HCMV infection, idiopathic thrombocytopenicpurpura and Basedow's disease.

Further, the compounds of Formula I are also useful for treating orpreventing renal diseases selected from interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome and diabeticnephropathy; nervous diseases selected from multiple myositis,Guillain-Barre syndrom, Meniere's disease and radiculopathy; enocrinediseases selected from hyperthyroidism; hematic diseases selected frompure red cell aplasia, aplastic anemia, hypoplastic anemia, autoimmunehemolytic anemia, agranulocytosis and anerythroplasia; bone diseasessuch as ostoporosis; respiraoty diseases selected from sarcoidosis,fibroid lung and idiopathic interstitial pneumonia; eye diseasesselected from herpetic keratitis, conical cornea, dystronphiaepithelialis cornease, corneal leukmas, ocular pemphigus, Mooren'sulcer, scleritis and Grave's ophthalmopathy; skin diseases selected fromdermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergicsensitivity and cutaneous T cell lymphoma; circulatory diseases selectedfrom arteriosclerosis, aortitis syndrome, polyarteritis nodosa andmyocardosis; collagen diseases selected from scleroderma, Wegener'sgranuloma and Sjogren's syndrome; adiposis; eosinophilic fascitis;periodontal disease; and muscular dystrophy.

The pharmaceutical compositions of this invention can be used in theform of a pharmaceutical preparation, for example, in solid, semisolidor liquid form, which contains one or more of the compounds of thepresent invention, as an active ingredient, in admixture with an organicor inorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The carriers which canbe used are water, glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate, talc, corn starch, keratin,colloidal silica, potato starch, urea and other carriers suitable foruse in manufacturing preparations, in solid, semisolid, or liquid form,and in addition auxiliary, stabilizing, thickening and coloring agentsand perfumes may be used. For example, the compounds of Formula I may beutilized with hydroxypropyl methylcellulose essentially as described inU.S. Pat. No. 4,916,138, issued Apr. 10, 1990, or with a surfactantessentially as described in EPO Publication 0,428,169. Oral dosage formsmay be prepared essentially as described by T. Hondo, et al.,Transplantation Proceedings, 1987, XIX, Supp. 6, 17-22. Dosage forms forexternal application may be prepared essentially as described in EPOPublication 0,423,714. The active object compound is included in thepharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of diseases.

For the treatment of these conditions and diseases caused byimmunoirregularity a compound of formula I may be administered orally,topically, parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections intravenous, intramuscular,intrasternal injection or infusion techniques.

Dosage levels of the compounds of the present invention are of the orderfrom about 0.005 mg to about 50 mg per kilogram of body weight per day,preferably from about 0.1 mg to about 10 mg per kilogram of body weightper day, are useful in the treatment of the above-indicated conditions(from about 0.7 mg to about 3.5 per patient per day, assuming a 70 kgpatient). In addition, the compounds of the present invention may beadministered on an intermittent basis; i.e. at daily, semiweekly,weekly, semi-monthly or monthly intervals.

The amount of active ingredient that may be combined with the carriermaterials to produce a signle dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 gm of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain from about 0.5 mg to about 500 mg of activeingredient, and preferably about 0.5 mg to about 100 mg of activeingredient. For external administration the compound of Formula I may beformulated within the range of, for example, 0.0001% to 60% by weight,preferably from 0.001 to 10% by weight, and most preferably from about0.0005 to 0.8% by weight.

It will be understood, however, that the specific dose level for anyparticular patient will depend on a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The Following examples are given for the purpose of illustrating thepresent invention and shall not be construed as being limitations on thescope or spirit of the instant invention.

EXAMPLE 117-Ethyl-1,14-dihydroxy-12-[2'-(4"-phenyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1 eq) andCu(OAc)₂ (2.8 mg, 0.014 mmol. 0.11 eq) in CH₂ Cl₂ (1 ml) in a 16 mLscrew-cap vial equipped with a magnetic stir-bar was added triphenylbismuth diacetate [prepared immediately prior to use by addition ofacetic acid (0.030 mL, 0.504 mmol, 4 eq) to a suspension of triphenylbismuth carbonate (127 mg, 0.253 mmol. 2 eq) in CH₂ Cl₂ (1 ml)]. Thereaction vessel was capped and the mixture stirred for five days. Thereaction mixture was diluted with several milliliters of saturatedaqueous NaHCO₃ and extracted 4 times with CH₂ Cl₂. The organic extractswere combined, dried over anhydrous Na₂ SO₄, filtered and concentratedin vacuo. The product was isolated by preparative TLC on silica gel(eluted with 3:4 EtOAc/hexanes to afford 46 mg of17-ethyl-1,14-dihydroxy12-[2'-(4"-phenyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR and mass spectralanalysis were consistent with the desired structure.)

EXAMPLE 2 A.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-phenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-phenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(341 ,4"-dihydroxycylohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (500 mg, 0.644 mmol, 1 eq) andCu(OAc)₂ (12 mg, 0.064 mmoo, 0.1 eq) in CH₂ Cl₂ (10 ml) in a 25 mlrecovery flask equipped with a magnetic stir-bar was added triphenylbismuth diacetate [prepared immediately prior to use by addition ofacetic acid (0.220 ml. 3860 mmol, 6 eq) to a suspension of triphenylbismutt carbonate (483 mg, 0.965 mmol, 1.5 eq) in CH₂ Cl₂ (10 ml)]. Thereaction flask was capped and the mixture stirred at room temperaturefor 6 hours. The flask was then fitted with a condenser and the mixturewas warmed to 40° C. After 40 hours the reaction mixture was cooled,diluted with saturated aqueous NaHCO₃ and extracted 4 times with CH₂Cl₂. The organic extracts were combined, dried over anhydrous Na₂ SO₄,filtered and concentrated in vacuo. the products were separated andpurified by flash column chromatography on silica gel [eluted with 4:1hexanes/acetone followed by preparative tLC on silica gel (eluted with2:1 hexanes/acetone] to yield 94 mg of 17-ethyl- 1,14-dihydroxy-12-[2'-(4"-phenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetra-methyl-11,28-dioxa-4-azatricylo[22.3.1.0.sup.4,9]-octacos-18-ene-2,3,10,16-tetraone and 110 mg of17-ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxycyclo-hexyl)-1-'-methylvinyl]-23,25-dimethoxy-13,19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 317-Ethyl-1,14-dihydroxy-12-[2'-(4'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1 eq) andCu(OAc)₂ (3 mg, 0.0165 mmol, 0.13 eq) in CH₂ Cl₂ (1 ml) in a 4 mLscrew-cap vial equipped with a magnetic stir-bar was addedtri(4-fluorophenyl)bismuth diacetate [prepared immediately prior to useby addition of acetic acid (0.030 mL, 0.504 mmol, 4 eq) to a suspensionof tri(4-fluorophenyl)bismuth carbonate (100 mg, 0.181 mmol, 1.4 eq) inCH₂ Cl₂ (1 mL)]. The reaction vessel was capped and the mixture stirredfor two days. The reaction mixture was diluted with several millilitersof saturated aqueous NaHCO₃ and extracted 2 times with CH₂ Cl₂. Theorganic extracts were combined, dried over anhydrous Na₂ SO₄, filteredand concentrated in vacuo. The product was isolated by preparative TLCon silica gel (eluted with 3:1 hexanes/EtOAc) to afford 39 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR and mass spectralanalysis were consistent with the desired structure).

EXAMPLE 417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-chlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.189 mmol, 1 eq) andCu(OAc)₂ (6.1 mg, 0.033 mmol, 0.17 eq) in CH₂ Cl₂ (2.5 ml) in a roundbottom flask equipped with a magnetic stir-bar was addedtri(4-chlorophenyl)bismuth diacetate [prepared immediately prior to useby addition of acetic acid (0.075 ml, 1.3 mmol, 6.9 eq) to a suspensionof tri(4-chlorophenyl)bismuth carbonate (200 mg, 0.331 mmol, 1.75 eq) inCH₂ Cl₂ (2.5 ml)]. The reaction flask was then fitted with a refluxcondenser and the mixture warmed to 40° C. After 20 hours the reactionmixture was cooled, diluted with saturated aqueous NaHCO₃ (10 mL) andextracted 4 times with CH₂ Cl₂. The organic extracts were dried overanhydrous Na₂ SO₄, filtered and concentrated in vacuo. The product wasseparated and purified two times by preparative TLC on silica gel(eluted with 2:1 hexanes/acetone) to give 40 mg17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-chlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl[-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, and massspectral analysis were consistent with the desired strcture).

EXAMPLE 517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1 eq) andCu(OAc)₂ (3 mg, 0.0165 mmol, 0.13 eq) in CH₂ Cl₂ (1 ml) in a 4 mL screwcap vial equipped with a magnetic stir-bar was added tri(4-tolyl)bismuthdiacetate [prepared immediately prior to use by addition of acetic acid(0.030 ml, 0.525 mmolo, 4.2 eq) to a suspension of tri(4-tolyl)bismuthcarbonate (130 mg, 0.234 mmol, 1.86 eq) in CH₂ Cl₂ (1 ml)]. The reactionvessel was capped and the mixture stirred for 20 hours at which time TLCanalysis showed the reaction to be incomplete. The mixture was treatedwith additional tri(4-tolyl) bismuth diacetate (0.234 mmol) and stirredfor 24 hours then poured into saturated aqueous NaHCO₃ and extracted 2times with CH₂ Cl₂. The organic extracts were combined, drried overanhydrous Na₂ SO₄, filtered and concentrated in vacuo. The product wasisolated by preparative TLC on silica gel (eluted with 2:1hexanes/EtOAc) to give 47 mg17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-methoxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, andmass spectral analysis were consistent with the desired structure.)

EXAMPLE 6 A.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-methylphenyloxy)-4"-hydroxycylohexy)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg, 0.257 mmol, 1 eq) andCu(OAc)₂ (10 mg, 0.055 mmol, 0.2 eq) in CH₂ Cl₂ (2 ml) in a round bottomflask equipped with a magnetic stir-bar was added tri(4-tolyl)bismuthdiacetate [prepared immediately prior to use by addition of acetic acid(0.075 ml, 1.31 mmol, 5.1 eq) to a suspension of tri(4-tolyl) bismuthcarbonate (300 mg, 0.553 mmol, 2.1 eq) in CH₂ Cl₂ (2 ml)]. The reactionflask was fitted with a reflux condenser and the mixture warmed to 40°C. for 5 hours then stirred without heating. After 18 hours the reactionmixture was diluted with saturated aqueous NaHCO₃ and extracted 2 timeswith CH₂ Cl₂. The organic extracts were combined, dried over anhydrousNa₂ SO₄, filtered and concentrated in vacuo. The products were separatedand purified by preparative TLC on silica gel (eluted with 2:1hexanes/acetone) to zfford 31 mg of17-ethyl-1,14-dihydroxy-12-[2-'-(3"-(4'"-methylphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and 42 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and ¹³ C NMR analysis wereconsistent with the desired structures).

EXAMPLE 7 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-phenoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

A stirred mixture of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.19 mmol, 1 eq) andCu(OAc)₂ (6.0 mg, 0.033 mmol, 0.17 eq) in CH₂ Cl₂ (2.5 ml) in a roundbottom flask equipped with a magnetic stir-bar and reflux condenser washeated to 40° C. then treated with tri(4-phenoxyphenyl)bismuth diacetate[prepared immediately prior to use by addition of acetic acid (0.075 mL,1.31 mmol, 6.9 eq) to a suspension of tri(4-phenoxyphenyl)bismuthcarbonate (225 mg, 0.29 mmol, 1.5 eq) in CH₂ Cl₂ (2.5 ml)]. After 18hours TLC analysis showed the reaction to be incomplete and additionaltri(4-phenoxyphenyl) bismuth diacetate (0.10 mmol) was added. Thereaction mixture was stirred with heating for 5 hours then cooled,diluted with saturated aqueous NaHCO₃, and extracted 2 times with CH₂Cl₂. The extracts were combined, dried over Na₂ SO₄, filtered, andconcentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (2:1 hexanes/acetone) to give 66 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-penoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, and massspectral analysis were consistent with the desired structure).

EXAMPLE 8 A.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-phenoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-phenoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.19 mmol, 1 eq) andCu(OAc)₂ (7 mg, 0.039 mmol, 0.21 eq) in CH₂ Cl₂ (2 mL) in a round bottomflask equipped with a magnetic stir-bar was addedtri(4-phenoxyphenyl)bismuth diacetate [prepared immediately prior to useby addition of acetic acid (0.070 ml, 1.22 mmol, 6.4 eq) to a suspensionof tri(4-phenoxyphenyl)bismuth carbonate (230 mg, 0.30 mmol., 1.58 eq)in CH₂ Cl₂ (2 mL)]. The reaction flask was fitted with a refluxcondenser and the mixture warmed to 40° C. After 4 hours the mixture wascooled, diluted with saturated aqueous NaHCO₃, and extracted 2 timeswith CH₂ Cl₂. The extracts were combined, dried over Na₂ SO₄, filtered,and concentrated in vacuo. The products were separated and purified 3×by preparative TLC on silica gel (3:2 hexanes/acetone) to afford 35 mgof17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-phenoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and 42 mg of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-phenoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl[-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, and mass spectalanalysis were consistent with the desired structures).

EXAMPLE 917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-1-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl[-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.19 mmol, 1 eq) andCu(OAc)₂ (6 mg, 0.033 mmol, 0.17 eq) in CH₂ Cl₂ (2 ml) in a round bottomflask equipped with a magentic stir-bar was added tri(1-naphthyl)bismuthdiacetate [prepared immediately prior to use by addition of acetic acid(0.070 ml, 1.22 mmol, 6.4 eq) to a suspension of tri(1-naphthyl)bismuthcarbonate (150 mg, 0.23 mmol, 1.2 eq) in CH₂ Cl₂ (2 ml)]. The reactionflask was then fitted with a reflux condenser and the mixture was warmedto 40° C. for 4 hours. After stirring an additional 16 hours at roomtemperature TLC analysis showed the reaction to be incomplete. Thereaction mixture was further treated with tri(1-naphthyl)bismuthdiacetate (0.15 mmol) and heated to 40° C. for 4 hours. The mixture wascooled, diluted with saturated aqueous NaHCO₃, and extracted 2 timeswith CH₂ Cl₂. The extracts were combined, dried over anhydrous Na₂ SO₄,filtered, and concentrated in vacuo. The product was isolated andpurified 2 times by preparation TLC on silica gel (3:1 hexanes/acetone)to give 38 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-1-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR analysis was consistentwith the desired structure).

EXAMPLE 10 A.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(naphth-1-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-1-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos- 18-ene-2,3,10,16-tetraone

To a stirred mixture of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,-10,16-tetraone (250 mg, 0.32 mmol, 1 eq) andCu(OAc)₂ (15 mg, 0.08 mmol, 25 eq) in CH₂ Cl₂ (5 ml) in a round bottomflask equipped with a magnetic stir-bar was added tri(1-naphthyl)bismuth diacetate [prepared immediately prior to use by addition ofacetic acid (0.100 ml, 1.75 mmol, 5.46 eq) to a suspension oftri(1-naphthyl) bismuth carbonate (350 mg, 0.54 mmol, 1.69 eq) in CH₂Cl₂ (5 ml)]. The reaction flask was fitted with a reflux condenser andthe mixture warmed to 40° C. for 5 hours then stirred at roomtemperature. After 16 hours the mixture was diluted with saturatedaqueous NaHCO₃ extracted 2 times with CH₂ Cl₂. The extracts werecombined, dried over anhydrous Na₂ SO₄, filtered, and concentrated invacuo. The products were separated and purified by preparative TLC onsilica gel (eluted with 3:1 hexanes/acetone) to yield 49 mg of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(naphth-1-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and 39 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-1-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR analysis was consistentwith the desired structure).

EXAMPLE 1117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.189 mmol, 1 eq) andCu(OAc)₂ (6 mg, 0.033 mmol, 0.17 eq) in CH₂ Cl₂ (2.5 mL) in a roundbottom flask equipped with a magnetic stir-bar was addedtri(2-naphthyl)bismuth diacetate [prepared immediately prior to use byaddition of acetic acid (0.075 ml, 1.31 mmol, 6.9 eq) to a suspension oftri(2-naphthyl)bismuth carbonate in CH₂ Cl₂ (2.5 ml)]. The reactionflask was fitted with a reflux condenser and the mixture warmed to 40°C. After 4 hours the heating was discontinued and the mixture stirred atroom temperature for 16 hours. The mixture was then diluted withsaturated aqueous NaHCO₃ and extracted 2 times with CH₂ Cl₂. Theextracts were combined, dried over anhydrous Na₂ SO₄, filtered, andconcentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (3:1 hexanes/acetone) to afford 32 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, and massspectral analysis were consistent with the desired structure).

EXAMPLE 12 A.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,-10,16-tetraone (250 mg, 0.32 mmol, 1 eq) andCu(OAc)₂ (10 mg, 0.055 mmol, 0.17 eq) in CH₂ Cl₂ (5.5 ml) in a roundbottom flask equipped with a magnetic stir-bar was added tri(2-naphthyl)bismuth diacetate [prepared immediately prior to use by addition ofacetic acid (0.100 ml, 1.75 mmol, 5.46 eq) to a suspension oftri(2-naphthyl)bismuth carbonate (350 mg, 0.538 mmol, 1.7 eq) in CH₂ Cl₂(5.5 ml)]. The reaction flask was fitted with a reflux condenser and themixture warmed to 40° C. for 4 hours then stirred at room temperature.After 3 days the reaction mixture was diluted with saturated aqueousNaHCO₃ and extracted 3 times with CH₂ Cl₂. The extracts were combined,dried over anhydrous Na₂ SO₄, filtered, and concentrated in vacuo. Theproducts were separated and purified by preparative TLC on silica gel(eluted with 3:1 hexanes/acetone) to give 63 mg of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(napth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and 49 mg of17-ethyl-1,14-dihyroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR was consistent with thedesired structure).

EXAMPLE 1317-Ethyl-1-hydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,-10,16-tetraone (300 mg, 0.39 mmol, 1 eq) andCu(OAc)₂ (15 mg, 0.083 mmol, 0.21 eq) in CH₂ Cl₂ (5 ml) in a roundbottom flask equipped with a magnetic stir-bar was addedtri(2-naphthyl)bismuth diacetate [prepared immediately prior to use byaddition of acetic acid to a suspension of tri(2-naphthyl)bismuthcarbonate (300 mg, 0.461 mmol, 1.2 eq) in CH₂ Cl₂ (5 ml)]. The reactionflask was fitted with a reflux condenser and the mixture warmed to 40°C. After 6 hours the mixture was allowed to cool to room temperature andstirred an additional 16 hours. The reaction mixture was diluted withsaturated aqueous NaHCO₃ and extracted 2 times with CH₂ Cl₂. Theextracts were combined, dried over anhydrous Na₂ SO₄, filtered, andconcentrated in vacuo. The product was isolated and purified bypreparative TLC (3:1 hexanes/acetone) to give 109 mg of17-ethyl-1-hydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and ¹³ C NMR analysis wereconsistent with the desired structure).

EXAMPLE 1417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-methoxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of tri-(6-methoxy-2-naphthyl)bismuth diacetate (52 mg,0.069 mmol, 1.1 eq) in methylene chloride (2 ml) in a 10 ml round bottomflask equipped with a stir bar was added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,9,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (50 mg, 0.063 mmol, 1 eq). To thereaction mixture was added a catalytic amount of Cu(OAc)₂ (approximately20 mg). The reaction flask was fitted with a reflux condenser and themixture was warmed to 40° C. After 1 hour the mixture was cooled,diluted with saturated aqueous NaHCO₃ and extracted 4 times with CH₂Cl₂. The organic extracts were combined, dried over anhydrous Na₂ SO₄,filtered and concentrated in vacuo. The product was isolated by twopreparative thin layer chromatographys on silica gel (firstchromatography eluted with 2:1 hexanes/acetone, isolated band at R_(f)=0.26 second chromatography eluted with 3.5% methanol/CH₂ Cl₂, isolatedband at R_(f) =0.62) to give 20 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-methoxy-naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and mass spectral analysiswere consistent with the desired structure).

EXAMPLE 14A General procedure for the preparation of triarylbismuthines

To a stirred suspension of magnesium (486 mg, 20 mmol) in drytetrahydrofuran (10 mL) is added slowly a solution of aryl halide (20mmol) in dry tetrahydrofuran (10 mL). If necessary the mixture is warmedgently to effect Grignard formation. To the stirred solution of theGrignard reagent is added a solution of bismuth trichloride (1.9 g, 6mmol) dissolved in dry tetrahydrofuran (20 mL). The resulting mixture isstirred for 24 hours. The reaction mixture is poured into a separatoryfunnel containing brine and extracted 4× with CH₂ Cl₂. The organicextracts were combined and dried over anhydrous Na₂ SO₄. The mixture wasfiltered and concentrated in vacuo. The triarylbismuthine is isolatedand purified by flash column chromatography on silica gel.

EXAMPLE 14B Tri(6-Methoxy-2-naphthyl)bismuth diacetate

To a stirred solution of tris(6-methoxynaphth-2-yl)bismuthine (100 mg,0.158 mmol) in CH₂ Cl₂ (8 mL) was added iodobenzene diacetate (200 mg,0.621 mmol). The CH₂ Cl₂ was removed in vacuo and the residue wasdissolved in several milliliters of 4:1 hexanes/acetone plus smallamount of CH₂ Cl₂. The solution was passed through a silica gel plug andeluted with 4:1 hexanes/acetone. The filtrate was concentrated in vacuo.The residue was dissolved in 4:1 hexanes/acetone plus small amount ofCH₂ Cl₂ and passed through a second silica gel plug and eluted with 4:1hexanes/acetone. The filtrate was concentrated in vacuo leaving 52 mgyellow residue that was used without further purification.

EXAMPLE 15 A.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-methoxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,2,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9] octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-methoxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone

To a solution of tri-(6-methoxy-2-naphthyl) bismuth diacetate (22 mg,0.028 mmol, 1 eq) in methylene chloride (2 ml) in a 10 mL round bottomflask equipped with a stir bar was added17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (22 mg, 0.028 mmol, 1 eq). To thereaction mixture was added a catalytic amount of Cu(OAc)₂ (approximately20 mg). The reaction flask was fitted with a reflux condenser and themixture was warmed to 40° C. After 1 hour the mixture was cooled,diluted with saturated aqueous NaHCO₃ and extracted 4 times with CH₂Cl₂. The organic extracts were combined, dried over anhydrous Na₂ SO₄,filtered and concentrated in vacuo. The product was isolated bypreparative thin layer chromatography on silica gel (eluted with 2:1hexanes/acetone) to give 7.1 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-methoxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,-10,16-tetraone (R_(f) =0.35) and 9 mg of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-methoxy-naphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.28). (¹ H NMR and massspectral analysis were consistent with the desired structures).

EXAMPLE 1617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1"-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(4-methoxyphenyl)bismuthine (200 mg, 0.377mmol) in CH₂ Cl₂ (4 mL) was added bis(trifluoroacetoxy)iodobenzene (162mg, 0.377 mmol). The mixture was stirred 5 minutes, then passed througha silica gel plug and eluted with EtOAc. The eluant was concentrated invacuo. The residue was dissolved in CH₂ Cl₂ (4 mL) in a 50 mL roundbottom flask equipped with a magnetic stir bar. To this stirred mixturewas added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (132 mg, 0.167 mmol) and Cu(OAc)₂ (10mg 0.055 mmol). The flask was capped and the mixture stirred 48 hours.The reaction was quenched by addition of saturated aqueous NaHCO₃ andextracted 44× with CH₂ Cl₂. The organic extracts were combined and driedover anhydrous Na₂ SO₄. The mixture was filtered and concentrated invacuo. The products were isolated by preparative TLC on silica gel (2:1hexanes/acetone) to afford 26.8 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone (R_(f)=0.35). (¹ H NMR and mass spectral analysis were consistent with thedesired structure).

EXAMPLE 1717-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1"-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(3-methoxyphenyl)bismuthine (200 mg, 0.377mmol) in CH₂ Cl₂ (3 mL) was added bis(trifluoroacetoxy)iodobenzene (162mg, 0.377 mmol). The mixture was stirred 5 minutes, then passed througha silica gel plug and eluted with EtOAc. The eluant was concentrated invacuo. The residue was dissolved in CH₂ Cl₂ (4 mL) in a 50 mL roundbottom flask equipped with a magnetic stir bar. To this stirred mixturewas added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (112 mg, 0.141 mmol) and Cu(OAc)₂ (10mg 0.055 mmol). The flask was capped and the mixture stirred 48 hours.The reaction was quenched by addition of saturated aqueous NaHCO₃ andextracted 44× with CH₂ Cl₂. The organic extracts were combined and driedover anhydrous Na₂ SO₄. The mixture was filtered and concentrated invacuo. The products were isolated by radial chromatography on silica gel(2 mm plate eluted with 3:1 hexanes/acetone) and then by preparative TLCon silica gel (eluted with 2:1 hexanes/acetone) to afford 78.4 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.40). (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 1817-Ethyl-1,4-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone

To a stirred solution oftris(6-tert-butyldimethylsilyloxynaphth-2-yl)bismuthine (100 mg, 0.215mmol) in CH₂ Cl₂ (4 mL) was added peracetic acid (0.05 mL, 0.238 mmol,32 wt % in dilute acetic acid). To this stirred solution was added THF(1 mL),17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol) and Cu(OAc)₂(catalytic amount). The flask was fitted with a reflux condenser and themixture was heated to 40° C. for 2 hours. The mixture was allowed tocool and was stirred 72 hours. The reaction was quenched with saturatedaqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts werecombined and dried over anhydrous Na₂ SO₄. The mixture was filtered andconcentrated in vacuo. The products were isolated by preparative TLC onsilica gel (eluted with 2:1 hexanes/acetone) to afford 47 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyl-dimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.56). (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 1917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (73 mg, 0.07 mmol) in CH₂ Cl₂ (2 mL)was added a solution of p-toluenesulfonic acid in methanol (2 mL, 10%solution). The flask was capped and the mixture stirred 4 hours. Thereaction was quenched with saturated aqueous NaHCO₃ and extracted 4×with CH₂ Cl₂. The organic extracts were combined and dried overanhydrous Na₂ SO₄. The mixture was filtered and concentrated in vacuo.The product was isolated by preparative TLC on silica gel (eluted with2:1 hexanes/acetone) to afford 44.2 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-4-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.23). (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 2017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone

To a stirred solution oftris(4-tert-butyldimethylsilyloxyphenyl)bismuthine (187 mg, 0.252 mmol)in CH₂ Cl₂ (4 mL) was added peracetic acid (0.053 mL, 0.252 mmol, 32 wt% solution in dilute acetic acid). To this stirred solution was added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol), CU(OAc)₂ (8.5mg, 0.046 mmol), and tetrahydrofuran (0.5 mL.). After stirring 48 hoursthe reaction mixture was quenched with saturated aqueous NaHCO₃ andextracted 4× with CH₂ Cl₂. The organic extracts were combined and driedover anhydrous Na₂ SO₄. The mixture was filtered and concentrated invacuo. The products were isolated by preparative TLC on silica gel(eluted with 2:1 hexanes/acetone) to afford 81 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-tert-buytl-dimethylsilyloxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ne-2,3,10,16-tetraone (R_(f) =0.49). (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 2117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-tert-butyldimethylsilyloxynaphth-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (74.8 mg, 0.075 mmol) in CH₂ Cl₂ wasadded a solution of p-toluenesulfonic acid in methanol (2 mL, 10% p-TsOHon methanol). The mixture was stirred 4 hours. The reaction mixture wasquenched with saturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂.The organic extracts were combined and dried over anhydrous Na₂ SO₄. Themixture was filtered and concentrated in vacuo. The products wereisolated by preparative TLC on silica gel (eluted with 2:1hexanes/acetone) to afford 52 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.25). (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 2217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylthiophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(4-methylthiophenyl)bismuthine (146 mg,0.252 mmol) in CH₂ Cl₂ was added peracetic acid (0.106 mL, 0.504 mmol).To this solution was added17-ethyl-1,14-diydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol), Cu(OAc)₂ (1 mg,0.061 mmol), and tetrahydrofuran (0.5 mL). The mixture was stirred for96 hours. The reaction mixture was quenched with saturated aqueousNaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts were combinedand dried over anhydrous Na₂ SO₄. The mixture was filtered andconcentrated in vacuo. The products were isolated by preparative TLC onsilica gel (eluted with 2:1 hexanes/acetone) to afford 15.5 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylthiophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.47). (¹ H NMR and massspectral were analysis consistent with the desired structure).

EXAMPLE 2317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(2-methylphenyl)bismuthine (50 mg, 0.014mmol) in CH₂ Cl₂ (2 mL) was added bis(trifluoroacetoxy)iodobenzene (45mg, 0.104 mmol). To this stirred solution was added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone (82 mg, 0.104 mmol),Cu(OAc)₂ (catalytic), and acetic acid (0.060 mL, 0.104 mmol). The flaskwas fitted with a reflux condenser and the mixture warmed to 40° C. andstirred overnight. The reaction mixture was cooled and diluted with CH₂Cl₂. The reaction mixture was quenched with saturated aqueous NaHCO₃ andextracted 4× with CH₂ Cl₂. The organic extracts were combined and driedover anhydrous Na₂ SO₄. The mixture was filtered and concentrated invacuo. The products were isolated by preparative TLC on silica gel(eluted with 2:1 hexanes/acetone) to afford 23.8 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"(2"'-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.46). (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 2417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3"'-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(3-methylphenyl)bismuthine (189 mg, 0.392mmol) in CH₂ Cl₂ (3 mL) was added bis(trifluoroacetoxy)iodobenzene (168mg, 0.392 mmol). To this stirred solution was added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.189 mmol) and Cu(OAc)₂(catalytic). The flask was capped and the mixture stirred overnight. Thereaction mixture was quenched with saturated aqueous NaHCO₃ andextracted 4× with CH₂ Cl₂. The organic extracts were combined and driedover anhydrous Na₂ SO₄. The mixture was filtered and concentrated invacuo. The products were isolated by radial chromatography on silica gel(eluted with 3:1 hexanes/ethyl acetate) to afford 70.9 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3"'-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and mass spectral analysiswere consistent with the desired structure).

EXAMPLE 2517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dimethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(3,4-dimethylphenyl)bismuthine (200 mg,0.381 mmol) in CH₂ Cl₂ (3 mL.) was addedbis(trifluoroacetoxy)iodobenzene (165 mg, 0.383 mmol). One mL of thissolution was transferred to a 10 mL flask. To this solution was added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.128 mmol) and Cu(OAc)₂(catalytic). The mixture was stirred overnight. The reaction mixture wasquenced with saturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. Theorganic extracts were combined and dried over anhydrous Na₂ SO₄. Themixture was filtered and concentrated in vacuo. The products wereisolated by radial chromatography on silica gel (eluted with 3.5%methanol/CH₂ Cl₂) and then purified by preparative TLC on silica gel(eluted with 3:1 hexanes/acetone) to afford 24.3 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3"',4"'-dimethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and mass spectral analysiswere consistent with the desired structure).

EXAMPLE 26 A.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(4"'-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4"'-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(4-methoxyphenyl)bismuthine (136 mg., 0.257mmol., 2 eq.) in methylene chloride (4 mL.) was added peracetic acid(0.054 mL., 0.257 mmol., 2 eq., 32% solution in dilute acetic acid). Tothis stirred solution was added b17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.126 mmol., 1 eq.), THF(0.5 mL.), and copper (II) acetate (7 mg., 0.038 mmol., 0.3 eq). Themixture was allowed to stir for 7 days. The reaction was quenched withsaturated aqueous NaCl plus 2 drops 2N HCl and extracted 4× withmethylene chloride. The organic extracts were combined, dried overanhydrous Na₂ SO₄, filtered, and concnetrated in vacuo. The productswere separated by preparative TLC on silica gel (2:1 hexanes/acetone).Each compound was repurified 2× by preparative TLC on silica gel (3:1hexanes/acetone then 3.5% MeOH/CH₂ Cl₂) affording 23.4 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4"'-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and 28.4 mg of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4"'-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structures).

EXAMPLE 27 A.17-Ethyl-1,14-dihydroxy-12-[2'(3"-(3"'-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3"'-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(3-methoxyphenyl)bismuthine (136 mg., 0.257mmol., 2 eq.) in methylene chloride (4 mL.) was added peracetic acid(0.054 mL., 2 eq., 32% solution in dilute acetic acid). To this stirredsolution was added17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.126 mmol., 1 eq.), THF(0.5 mL.), and copper (II) acetate (7 mg., 0.038 mmol., 0.3 eq.). Themixture was allowed to stir for 7 days. The reaction was quenched withsaturated aqueous NaCl plus 2 drops 2N HCl and extracted 4× withmethylene chloride. The organic extracts were combined, dried overanhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productswere separated by preparative TLC on silica gel (2:1 hexanes/acetone).Each compound was repurified 2× by preparative TLC on silica gel (2:1hexanes/acetone then 3.5% MeOH/CH₂ Cl₂) affording 27 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and 35 mg of17-ethyl-1,14-dihydroxy-12-[2'-[3"-(3'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and mass spectral analysiswere consistent with the desired structures).

EXAMPLE 28 A.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-tertbutyldimethylsilyloxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4"'-tertbutyldimethylsilyloxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethyoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-19-ene-2,3,10,16-tetraone

To a stirred solution oftri(4-tert-butyldimethylsilyloxyphenyl)bismuthine (213 mg., 0.257 mmol.,2 eq.) in methylene chloride (4 mL.) was added peracetic acid (0.054mL., 0.257 mmol., 2 eq. 32% solution in dilute acetic acid). To thisstirred solution was added17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.126 mmol., 1 eq.), THF(0.5 mL.), and copper (II) acetate (7 mg., 0.038 mmol., 0.3 eq.). Themixture was allowed to stir for 7 days. The reaction was quenched withsaturated aqueous NaCl plus 2 drops 2N HCl and extracted 4× withmethylene chloride. The organic extracts were combined, dried overanhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productswere separated by preparative TLC on silica gel (2:1 hexanes/acetone)affording 41.9 mg. of17-ethyl-1,14-dihydroxy-12-[2'-(4"(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and 42.5 mg. of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-4"-hydroxycylohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structures).

EXAMPLE 2917-Ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (42.5 mg) in CH₂ Cl₂ (1.5 mL.) at 0°C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL.of a 10% w/v solution). The mixture was stirred 3H at 0° C. and then 3Hat room temperature. The reaction mixture was quenched with saturatedaqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts werecombined and dried over anhydrous Na₂ SO₄. The mixture was filtered andconcentrated in vacuo. The product was isolated by preparative TLC onsilica gel (eluted with 2:1 hexanes/acetone) affording 25.7 mg of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and mass spectral anaylsiswere consistent with the desired structure).

EXAMPLE 3017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18 -ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (41.9 mg) in CH₂ Cl₂ (1.5 mL.) at 0°C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL.of a 10% w/v solution). The mixture was stirred 3H at 0° C. and then 3Hat room temperature. The reaction mixture was quenched with saturatedaqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts werecombined and dried over anhydrous Na₂ SO₄. The mixture was filtered andconcentrated in vacuo. The product was isolated by preparative TLC onsilica gel (eluted with 2:1 hexane/acetone) affording 23.9 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and mass spectral analysisare consistent with the desired structure).

EXAMPLE 31 A.17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxy-naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2.3.10.16-tetraone

To a stirred solution oftri(6-tert-butyldimethylsilyloxynaphth-2-yl)bismuthine (252 mg., 0.257mmol., 2 eq.) in methylene chloride (4 mL.) was added peracetic acid(0.054 mL., 0.257 mmol., 2 eq., 32% solution in dilute acetic acid). Tothis stirred solution was added17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.126 mmol., 1 eq.), THF(0.5 mL.), and copper (II) acetate (7 mg., 0.038 mmol., 0.3 eq.). Themixture was allowed to stir for 7 days. The reaction was quenched withsaturated aqueous NaCl plus 2 drops 2N HCl and extracted 4× withmethylene chloride. The organic extracts were combined, dried overanhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productswere separated by preparative TLC on silica gel (2:1 hexanes/acetone)affording 39.8 mg. of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6"'-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and 41.6 mg. of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-4"-hydroxycylohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and mass spectral analysiswere consistent with the desired structures).

EXAMPLE 3217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (39.8 mg) in CH₂ Cl₂ (1.5 mL.), at 0°C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL.of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C. and then1.75 h at room temperature. The reaction mixture was quenched withsaturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined and dried over anhydrous Na₂ SO₄. The mixture wasfiltered and concentrated in vacuo. The product was isolated bypreparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone)affording 17 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and mass spectral analysiswere consistent with the desired structure).

EXAMPLE 3317-Ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (41.6 mg) in CH₂ Cl₂ (1.5 mL.) at 0°C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL.of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C. and then1.75 h at room temperature. The reaction mixture was quenched withsaturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined and dried over anhydrous Na₂ SO₄. The mixture wasfiltered and concentrated in vacuo. The product was isolated bypreparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone)affording 20.8 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and mass spectral analysiswere consistent with the desired structure).

EXAMPLE 3417-Ethyl-1,14-dihydroxy-12-[2-(4"-(ethoxycarbomethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg., 0.253 mmol., 1 eq.) indiethyl ether (6 mL.) was added boron trifluoride etherate (0.009 mL.,0.073 mmol., 0.3 eq.) and ethyl diazoacetate (0.080 mL., 0.760 mmol., 3eq.). The reaction mixture was stirred 12 h. The reaction mixture wasquenched with saturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂.The organic extracts were combined and dried over anhydrous Na₂ SO₄. Themixture was filtered and concentrated in vacuo. The products wereisolated by preparative TLC on silica gel (3:2 EtOAc/hexanes) and asecond preparative TLC (eluted 2× with 3:1 hexanes/acetone) affording24.7 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(ethoxycarbomethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR and mass spectralanalysis were consistent with the desired structure).

EXAMPLE 3517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dichlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(3,4-dichlorophenyl)bismuthine (163 mg.,0.25 mmol.) in CH₂ Cl₂ (2 mL.) was addedbis(trifluoroacetoxy)iodobenzene (107 mg., 0.25 mmol.). The mixture wasstirred for 15 minutes then treated with Cu(OAc)₂ followed by a solutionof17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.126 mmol.) in CH₂ Cl₂ (2mL.). After stirring an additional 2 hours the reaction mixture wasquenched by addition of saturated aqueous NaHCO₃ and extracted 2× withCH₂ Cl₂. The organic extracts were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The product was separated andpurified by preparative TLC on silica (eluted with 3:1 Hexane/Acetone)to give 51 mg 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dichlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (¹ H NMR, ¹³ H NMR, and mass spectralanalysis are consistent with the desired structure).

EXAMPLE 3617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(phenanthr-9-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution on tri(9-phenanthryl)bismuthine (150 mg., 0.20mmol) in CH₂ Cl₂ (3 mL) was added peracetic acid (0.050 mL, 0.22 mmol,32 wt. % solution in dilute acetic acid). After 15 minutes the solutionwas treated with17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol) and Cu(OAc)₂ (10mg, 0.055 mmol) and stirred for 18 hours. The reaction mixture wasquenched with saturated aqueous NaHCO₃ and extracted 3× with CH₂ Cl₂.The extracts were combined, dried with Na₂ SO₄, filtered andconcentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (eluted with 2:1 hexane/acetone to give 12mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(phenanthr-9-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 octacos-18-ene-2,3,10,16-tetraone (¹ H NMR was consistentwith the desired structure).

EXAMPLE 3717-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-methylenedioxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2.3.10.16-tetraone

To a stirred solution of tri(3,4-methylenedioxyphenyl)bismuthine (150mg., 0.26 mmol) in CH₂ Cl₂ (2 mL) was added peracetic acid (0.060 mL,0.26 mmol, 32 wt % solution in dilute acetic acid). After approximately10 minutes the solution was treated with Cu(OAc)₂ (25 mg, 0.138 mmol)and17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol) and stirred for18 hours. The reaction mixture was quenched with saturated aqueousNaHCO₃ and extracted 2× with CH₂ Cl₂. The extracts were combined, driedwith anhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productwas isolated and purified by preparative TLC on silica gel (eluted with2:1 Hexane/Acetone) to give 37 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-methylenedioxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]octacos-18-ene-2,3,10,16-tetraone (¹ H NMR and mass spectral analysiswere consistent with the desired structure).

EXAMPLE 3817-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'",3'"-dihydrobenzofuran-5-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2.3.10.16-tetraone

To a stirred solution of tri(2,3-dihydrobenzofuran-5-yl)bismuthine (32mg, 0.056 mmol) in CH₂ Cl₂ (1 mL) was added peracetic acid (0.020 mL,0.09 mmol, 32 wt % solution in dilute acetic acid). After approximately15 minutes the solution was treated with Cu(OAc)₂ (20 mg, 0.11 mmol) and17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (50 mg, 0.06 mmol) and stirred forthree days. The reaction mixture was quenched with saturated aqueousNaHCO₃ and extracted with CH₂ Cl₂. The extracts were combined, driedwith anhydrous Na₂ SO₄, filtered and concentrated in vacuo. The productwas purified by preparative TLC on silica gel (eluted with 2:1Hexane/acetone) to give 14 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'",3'"-dihydrobenzofuran-5-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone characterized by (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 3917-Allyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

A mixture of17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18ene-2,3,10,16-tetraone (400 mg, 0.5 mmol) and Cu(OAc)₂ (35mg, 0.19 mmol) in CH₂ Cl₂ (6 mL) was warmed to 40° C. for 15 minutesthen treated with tri(2-naphthyl)bismuth diacetate [prepared immediatelyprior to use by addition of acetic acid (0.18 mL, 3 mmol) to asuspension of tri(2-naphthyl)bismuth carbonate (600 mg, 0.92 mmol) inCH₂ Cl₂ (6 mL)]. Heating was maintained for 4 hours after which time themixture was stirred at room temperature for 18 hours. The reactionmixture was quenched with saturated aqueous NaHCO₃ and extracted withCH₂ Cl₂. The extracts were combined, dried with Na₂ SO₄, filtered andconcentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (eluted with 3:1 Hexane/Acetone) to give234 mg of17-allyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18ene-2,3,10,16-tetraone (¹ H NMR and mass spectral analysiswere consistent with the desired structure).

EXAMPLE 4017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'",4'"-benzodioxane-6-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(1,4-benzodioxan-6-yl)bismuthine (90 mg,0.146 mmol) in CH₂ Cl₂ (1 mL) was added peracetic acid (0.030 mL, 0.13mmol, 32 wt % in dilute acetic acid). After 20 minutes the mixture wastreated with17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol) followed byCu(OAc)₂ (15 mg, 0.08 mmol) and stirred for 2 days. The reaction mixturewas quenched with saturated aqueous NaHCO₃ and extracted with CH₂ Cl₂.The extracts were combined, dried with Na₂ SO₄, filtered andconcentrated in vacuo. The product was purified by preparative TLC onsilica gel (eluted with 4% CH₃ OH in CH₂ Cl₂) to give 18 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1'",4'"-benzodioxane-6-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]octacos-18-ene-2,3,10,16-tetraone (¹ H NMR and mass spectral analysiswere consistent with the desired structure).

EXAMPLE 40B17-Ethyl-1-hydroxy-12-[2'-(4'"-dimethylamino)phenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone (A) and17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-dimethylamino)phenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone (B)

Peracetic acid (850 ml) was added to a solution oftri(4-dimethylaminophenyl)bismuthine (1.27 g) in 30 ml tetrahydrofuran.After 10 minutes17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]-octacos-18-ene-2,3,10,16-tetraone (100 mg) was added followed bycopper acetate (280 mg) and the mixture heated to 60° C. for 48 hours.The mixture was then cooled and quenched by pouring into saturatedsodium bicarbonate, extracting with ether (3×25 ml). The combinedorganic washes were dried with magnesium sulphate and concentrated. Thecrude residue was purified by column chromatography on silica geleluting with 70% hexane:30% ethyl acetate to give the title compounds A(93 mg) and B (102 mg) each as white solids.

EXAMPLE 4117-Ethyl-1,2,14-trihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-3,10,16-trione

A solution of 1,2-diiodoethane (42 mg, 0.15 mmol) in dry THF (1 mL) wasadded dropwise to a stirred mixture of samarium metal (46.5 mg, 0.31mmol) in dry THF (1 mL) and stirred for 1.5 hours. The reaction mixturewas then cooled to -78° C. (dry ice/acetone) and treated with a solutionof 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.109 mmol) in 1:1 THF/CH₃OH. The mixture was maintained at -78° C. for 15 minutes then allowed towarm to room temperature. The reaction was quenched with cold saturatedaqueous K₂ CO₃ and quickly extracted with CH₂ Cl₂. The extracts werecombined, dried with Na₂ SO₄, filtered and concentrated in vacuo.Purified by preparative TLC on silica gel (eluted with 7% CH₃ OH in CH₂Cl₂) to give 22 mg of17-ethyl-1,2,14-trihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-3,10,16-trione (¹ H NMR and mass spectral analysis areconsistent with the desired structure).

EXAMPLE 4217-Ethyl-1,14-dihydroxy-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg in 3.0 ml 33% methylenechloride in cyclohexane), allyl trichloroacetimidate (88 μl neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (4.5 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 18 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (156 mg).

MASS: (FAB) 838 (M+Li)

Partial ¹ H NMR δ: 5.82 (m, 1H); 4.85 (m), 4.20 (brs, 1H); 4.59 (brdJ=4.5 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.03 (dt J=4.0, 1.0 Hz, 2H).

EXAMPLE 4317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-butynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylenechloride in cyclohexane), 2-butynyl trichloroacetimidate (20 μl neat)was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 16 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compound (17 mg).

MASS: (FAB) 843 (M+Na)

Partial ¹ H NMR δ: 5.32 (Major amide rotamer), 5.29 (minor amiderotamer) (brd J=3.0 Hz, 1H); 4.83m, 4.21M (brs, 1H); 4.59 (brd J=4.0 Hz,1H); 4.42 (brd J=14.0 Hz, 1H); 4.26 (m, 2H); 1.83 (t J=2.0 Hz, 3H).

EXAMPLE 4417-Ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylenechloride in cyclohexane), cinnamyl trichloroacetimidate (26 μl neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 15 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×5 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compound (10 mg).

MASS: (FAB) 907 (M+Na)

Partial ¹ H NMR δ: 6.62 (d J=15 Hz, 1H); 6.30 (dt J=15, 6.0 Hz, 1H);5.33M, 5.19 m (brd J=3.0 Hz, 1H); 4.83m, 4.21M (brs, 1H); 4.58 (brdJ=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.30 (d J=6.0 Hz, 2H).

EXAMPLE 4517-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (37 mg in 2 ml ethanol) was added 4mg of 5% rhodium on carbon catalyst. The reaction flask was fitted witha hydrogen balloon, evacuated and recharged with hydrogen (3 times) andstirred at room temperature. After 1.5 hours, the mixture was filteredover Celite, concentrated and purified by preparative TLC on silica gel(ethyl acetate:hexane (1:2)+1% methanol) to give the title compound(19.5 mg).

MASS: (FAB) 932 (M+Na); 916 (M+Li)

Partial ¹ H NMR δ: 5.31M, 5.28m (d J=3.0 Hz, 1H); 4.85m, 4.21M (brs,1H); 4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.69 (t J=8.0 Hz,2H).

EXAMPLE 46 A.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-allyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-allyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg in 1.5 ml 33% methylenechloride in cyclohexane), allyl trichloroacetimidate (53 μl neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 3 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (21 mg 4"-ether; 17 mg3"-ether).

A. (4"-ether):

Partial ¹ H NMR δ: 5.93 (m, 1H); 4.87m, 4.19M (brs, 1H); 4.59 (brd J=4.0Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.67 (brd J=3.7 Hz, 1H).

B. (3"-ether):

Partial ¹ H NMR δ: 5.93 (m, 1H); 4.83m, 4.23M (brs, 1H); 4.59 (brd J=4.0Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.63 (brs, 1H).

EXAMPLE 47 A.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-isopropoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-isopropoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (110 mg in 1.5 ml 33% methylenechloride in cyclohexane), isopropyl trichloroacetimidate (52 μl neat)was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 3 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organic were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (15 mg 4"-ether; 16 mg3"-ether).

A. (4"-ether):

MASS: (FAB) 826 (M+Li)

Partial ¹ H NMR δ: 5.31 (d J=3.0 Hz, 1H); 4.85m, 4.18M (brs, 1H); 4.58(brd J=4.0 Hz, 1H); 4.40 (brd J=14 Hz, 1H); 2.63 (brs, 1H).

B. (3"-ether):

MASS: (FAB) 826 (M+Li)

Partial ¹ H NMR δ: 5.31 (d J=3.0 Hz, 1H); 4.81m, 4.22M (brs, 1H); 4.58(brd J=4.0 Hz, 1H); 4.40 (brd J=14 Hz, 1H); 2.60 (brs, 1H).

EXAMPLE 48 A.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-sec-butenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg in 3 ml 33% methylenechloride in cyclohexane), sec-butenyl trichloroacetimidate (62 μl neat)was added and the reagents allows to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 15 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×8 ml). The combined organic were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (11 mg 4"-ether; 3"-ether).

A. (4"-ether):

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 4.58 (brd J=3.0 Hz, 1H); 4.87m, 4.18M(brs, 1H); 4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

B. (3"-ether):

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.31 (brs, 1H); 4.82m, 4.22M (brs, 1H);4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

EXAMPLE 49 A.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(trans-2'"-butenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-(trans-2'"-butenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (115 mg in 3 ml 33% methylenechloride in cyclohexane), trans-2-butenyl trichloroacetimidate (48 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) wad added slowly via syringeand the mixture stirred at room temperature. After 35 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×8 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparation TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (14 mg 4"-ether; 12 mg3"-ether).

A. (4"-ether):

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.31 (brd J=3.0 Hz, 1H); 4.86m, 4.19M(brs, 1H); 4.59 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.68 (brs,1H).

B. (3"-ether):

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.30 (brs, 1H); 4.81m, 4.22M (brs, 1H);4.59 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.64 (brs, 1H).

EXAMPLE 50 A.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg in 2 ml methylene chloride),3-methyl-2-butenyl trichloroacetimidate (39 μl neat) was added and thereagents allowed to mix for 5 minutes. Camphorsulfonic acid (5 mg) wasadded and the mixture stirred at room temperature. After 21 hours thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×8 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (24 mg 4"-ether; 21 mg3"-ether).

A. (4"-ether):

MASS: (FAB) 845 (M+Na)

Partial ¹ H NMR δ: 4.87m, 4.19M (brs, 1H); 4.58 (brd J=4.0 Hz, 1H); 4.41(brd J=14 Hz, 1H); 2.70 (brs, 1H); 1.75 (s, 3H); 1.67 (s, 3H).

B. (3"-ether):

MASS: (FAB) 845 (M+Na)

Partial ¹ H NMR δ: 4.82m, 4.23M (brs, 1H); 4.58 (brd J=4.0 Hz, 1H); 4.41(brd J=14 Hz, 1H); 2.67 (brs, 1H); 1.75 (s, 3H); 1.67 (s, 3H).

EXAMPLE 51 A.17-Ethyl-1,14-dihydroxy-12-[2-(3"-hydroxy-4"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2-(4"-hydroxy-3"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg in 3 ml 33% methylenechloride in cyclohexane), 2-methylpropenyl trichloroacetimidate (84 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 1 hour the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×8 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate : hexane(1:1) + 1% methanol) gave the title compounds (34 mg 4"-ether; 24 mg3"-ether).

A. (4"-ether):

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.32 (brs, 1H); 4.87 (brs, 1H); 4.59 (brs, 1H); 4.41(brd J=14 Hz, 1H); 4.19M (brs, 1H); 2.60 (brs, 1H); 1.74 (s, 3H).

B. (3"-ether):

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.32 (brs, 1H); 4.87 (brs, 1H); 4.81 m, 4.23M (brs,1H); 2.63 (brs, 1H); 1.74 (s, 3H).

EXAMPLE 5217-Ethyl-1,14-dihydroxy-12-[2'-(3"-cinnamyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.31.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33% methylenechloride in cyclohexane), cinnamyl trichloroacetimidate (52 μl neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 15 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×8 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compound (17 mg).

MASS: (FAB) 893 (M+Na)

Partial ¹ H NMR δ: 6.61 (d J=15 Hz, 1H); 6.28 (dt J=15, 6.0 Hz, 1H);5.32 m, 5.19M (brd J=3.0 Hz); 4.82 m, 4.22M (brs,1H); 4.52 (brd J=4.0Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.66 (brs, 1H).

EXAMPLE 5317-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-isopropoxycyclohexyl)-1'-methylviinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azaticyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]octacos-18-ene-2,3,10,16-tetraone (69 mg in 3 ml 33% methylene chloridein cyclohexane), isopropyl trichloroacetimidate (22 μl neat) was addedand the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonicacid (2 μl neat) was added slowly via syringe and the mixture stirred atroom temperature. After 24 hours the reaction was quenched by theaddition of saturated sodium bicarbonate and extracted with ethylacetate (3×8 ml). The combined organics were washed with brine and driedover magnesium sulfate. Purification of the concentrate by preparativeTLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave thetitle compound (12 mg).

MASS: (FAB) 803 (M+Li)

Partial ¹ H NMR δ: 4.87 (brd J=10 Hz, 1H); 4.56 (d J=4.0 Hz, 1H); 4.42m, 4.33 M (brs, 1H); 2.61 (brs, 1H); 1.16 (d J=7.0 Hz, 6H).

EXAMPLE 54 A.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-sec-butenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1,14-dihydroxy-12-[2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 3 ml 33%methylene chloride in cyclohexane), sec-butenyl trichloroacetimidate (62μl neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 15 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×8 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (11 mg 4"-ether; 13 mg3"-ether).

A. (4"-ether):

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.32 (brd J=3.0 Hz, 1H); 4.87m, 4.18M(brs, 1H); 4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

B. (3"-ether):

MASS (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.31 (brs, 1H); 4.82m, 4.22M (brs, 1H);4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

EXAMPLE 5517-Ethyl-1-hydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33% methylenechloride in cyclohexane), cinnamyl trichloroacetimidate (54 μl neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. At 30 minutes the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×8 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (45 mg).

MASS: (FAB) 891 (M+Li)

Partial ¹ H NMR δ: 6.62 (d J=15 Hz, 1H); 6.31 (dt J=15, 6.0 Hz, 1H);4.56 (brd J=4.0 Hz, 1H); 4.31 (d J=6.0 Hz, 2H).

EXAMPLE 5617-Ethyl-1-hydroxy-12-[2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methyvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (16 mg in 2 ml ethanol) was added 2mg of 5% rhodium on carbon catalyst. The reaction flask was fitted witha hydrogen balloon, evacuated and recharged with hydrogen (3 times) andstirred at room temperature. After 30 minutes, the mixture was filteredover diatomacous earth, concentrated and purified by preparative TLC onsilica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the titlecompound (5.5 mg).

MASS: (FAB) 916 (M+Na)

Partial ¹ NMR δ: 4.58 (brd J=4.0 Hz, 1H); 4.42m, 4.32M (brs, 1H); 4.40(brd J=14 Hz, 1H); 2.69 (t J=8.0 Hz, 2H).

EXAMPLE 5717-Ethyl-1,14-dihydroxy-12-[2'-(4"-sec-phenethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.9⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (75 mg in 3 ml 33% methylene chloridein cyclohexane), sec-phenethyl trichloroacetimidate (38 μl neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid 3 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 30 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×10 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (13 mg).

MASS: (FAB) 918 (M+Na) 902 (M+Li)

Partial ¹ H NMR δ: 5.28 (m, 1H); 4.56 (m, 1H); 4.41 (brd J=14 Hz, 1H);4.86m, 4.20M (brs, 1H).

EXAMPLE 5817-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-methylcinnamyloxy)-3"-methoxyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexy)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylenechloride in cyclohexane), 2-methylcinnamyl trichloroacetimidate (28 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (3 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 20 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×10 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (9 mg).

MASS: (FAB) 944 (M+Na)

Partial ¹ H NMR δ: 6.53 (brs, 1H); 5.32 (brd, J=3 Hz, 1H); 4.85m, 4.21M(brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.16 (brs,2H); 1.90 (brs, 3H).

EXAMPLE 5917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methyl-2'",4'"-hexadienyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricycl[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylenechloride in cyclohexane), 4-methyl-2,4-hexadienyl trichloroacetimidate(97 μl neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (5 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 4 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×20 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (8 mg).

MASS: (FAB) 892 (M+Li)

Partial ¹ H NMR δ: 6.25 (d J=15 Hz, 1H); 5.64 (dt J=15,7 Hz, 1H); 5.31(brd J=3 Hz, 1H); 4.83m, 4.21M (brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41(brd J=14 Hz, 1H); 4.18 (brd J=7 Hz, 2H).

EXAMPLE 6017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-methoxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetaone (200 mg in 6ml 33% methylene chloride in cyclohexane), p-methoxycinnamyltrichloroacetimidate (117 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (3 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 20minutes the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (16mg).

MASS: (FAB) 960 (M+Na) 944 (M+Li)

Partial ¹ H NMR δ: 7.29 (brd J=9 Hz, 2H); 6.85 (brd J=9 Hz, 2H); 5.32M,5.19m (brd J=3 Hz, 1H); 4.84m, 4.21M (brs, 1H); 4.61 (brd J=5 Hz, 2H);4.41 (brd J=14 Hz, 1H).

EXAMPLE 6117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-methylenedioxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylenechloride in cyclohexane), 3',4'-methylenedioxycinnamyltrichloroacetimidate (122 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (3 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 30minutes the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (10mg).

MASS: (FAB) 974 (M+Na)

Partial ¹ H NMR δ: 6.54 (d J=16 Hz, 1H); 6.14 (dt J=16,6 Hz, 1H); 5.95(s, 2H) 5.33M, 5.19m (brd J=3 Hz, 1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brdJ=14 Hz, 1H); 4.27 (brd J=6 Hz, 2H).

EXAMPLE 6217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'",4'"-dimethyl-2'"-trans-pentenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylenechloride in cyclohexane), 4,4-dimethyl-2-trans-pentenyltrichloroacetimidate (98 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (10 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After1.5 hours the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (17mg).

MASS: (FAB) 894 (M+Li)

Partial ¹ H NMR δ: 5.70 (d J=16 Hz, 1H); 5.48 (dt J=16,7 Hz, 1H); 5.31(brd J=3 Hz, 1H); 4.84m, 4.21M) (brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41(brd J=14 Hz, 1 H); 4.18 (brd J=7 Hz, 2H); 1.01 (s, 9H).

EXAMPLE 6317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-cyclohexyl-2'"-trans-propenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylenechloride in cyclohexane), 3-cyclohexyl-2-trans-propenyltrichloroacetimidate (108 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 1hour the reaction was quenched by the additio of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (20mg).

MASS: (FAB) 936 (M+Na)

Partial ¹ H NMR δ: 5.32M, 5.19m (brd J=3 Hz, 1H); 4.84m, 4.21M (brs,1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.06 (brd J=5 Hz,2H).

EXAMPLE 6417-Ethyl-1,14-dihydroxy-12-[2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylenechloride in cyclohexane), p-fluorocinnamyl trichloroacetimidate (112 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 20 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×20 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (33 mg).

MASS: (FAB) 932 (M+Li)

Partial ¹ H NMR δ: 7.37 (d J=6 Hz, 1H); 7.31 (d J=6 Hz, 1H); 7.01 (d J=9Hz, 1H); 6.96 (d J=9 Hz, 1H); 6.57 (d J=16 Hz, 1H); 6.21 (dt J=16, 6 Hz,1H); 5.32M, 5.19m (brd J=3 Hz, 1H); 4.83m, 4.21M (brs, 1H); 4.59 (brdJ=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.29 (d J=6 Hz, 2H).

EXAMPLE 6517-Ethyl-1,14-dihydroxy-12-[2'-(4"-p-chlorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetaone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylenechloride in cyclohexane), p-chlorocinnamyl trichloroacetimidate (119 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 30 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×20 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (34 mg).

MASS: (FAB) 948 (M+Li)

Partial ¹ H NMR δ: 6.58 (d J=16 Hz, 1H); 6.27 (dt J=16, 6 Hz, 1H);5.32M, 5.19m (brd J=3 Hz, 1H); 4.84m, 4.21M (brs, 1H); 4.59 (brd J=4 Hz,1H); 4.41 (brd J=14 Hz, 1H); 4.30 (d J=6 Hz, 1H).

EXAMPLE 6617-Ethyl-1,14-dihydroxy-12-[2'-(4"-p-bromocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylenechloride in cyclohexane), p-bromocinnamyl trichloroacetimidate (135 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 1 hour the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×20 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (19 mg).

MASS: (FAB) 984, 986 (M+)

Partial ¹ H NMR δ: 7.42 (d J=9 Hz, 2H); 7.20 (d J=9 Hz, 2H); 6.56 (dJ=16 Hz, 1H); 6.29 (dt J=16, 6 Hz, 1H); 5.31M, 5.19m (brd J=3 Hz, 1H);4.85m, 4.21M (brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H);4.28 (d J=6 Hz, 2H).

EXAMPLE 6717-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-p-fluorophenpropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,310,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (22 mg in 2 ml ethanol) was added 6mg of 5% rhodium on carbon catalyst. The reaction flask was fitted witha hydrogen balloon, evacuated and recharged with hydrogen (3 times) andstirred at room temperature. After 45 minutes, the mixture was filteredover Celite, concentrated and purified by preparative TLC on silica gel(ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (7.5mg).

MASS: (FAB) 934 (M+Li)

Partial ¹ H NMR δ: 7.16 (d J=6 Hz, 1H); 7.12 (d J=6 Hz, 1H); 6.97 (d J=9Hz, 1H); 6.92 (d J=9 Hz, 1H); 5.32M, 5.19m (brd J=3 Hz, 1H); 4.85m,4.21M (brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.67 (tJ=8 Hz, 2H).

EXAMPLE 6817-Ethyl-1-hydroxy-12-[2'-(3",4"-diallyloxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]-octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(3",4"-diallyloxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]-octacos-18-ene-2,3,10,16-tetraone (20 mg in 0.75 ml 33% methylenechloride in cyclohexane), allyl trichloroacetimidate (16 μL neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2.0 μL neat) was added slowly via syringeand the mixture stirred at room temperature. After 5 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:3)+1% methanol) gave the title compound (6.8 mg). (¹ H NMR wasconsistent with the desired structure).

EXAMPLE 6917-Ethyl-1-hydroxy-12-[2'-(3",4"-dipropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]-octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(3",4"-dipropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]-octacos-18-ene-2,3,10,16-tetraone(6.8 mg in 600 μl ethyl acetate) was added 4 mg of 5% rhodium on carboncatalyst. The reaction flask was fitted with a hydrogen balloon,evacuated and recharged with hydrogen (3 times) and stirred at roomtemperature. After 25 minutes, the mixture was filtered over Celite,concentrated and purified by flash chromatography on silica gel (ethylacetate:hexane (1:3)+1% methanol) to give the title compound (4.5 mg).

MASS: (FAB) 852 (M+Li)

Partial ¹ H NMR δ: 4.59 (brm, 1H); 4.42m, 4.33M (brs, 1H); 4.41 (brd,J=14 Hz, 1H); 3.54 (m, 4H).

EXAMPLE 7017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (2.35 g) in dry methylene chloride(20 ml) was added an excess of 2,6-lutidine (1.04 ml) and the mixturewas stirred at room temperature. After 10 minutes,tert-butyldimethylsilyl trifluoromethanesulfonate (1.50 ml) was addedvia syringe. After 1 hour the reaction mixture was diluted with ethylacetate, extracted from saturated sodium bicarbonate, washed with brineand the organic phase dried over magnesium sulfate. Removal of thesolvent in vacuo and flash chromatography on silica gel (ethyl acetate:hexane (1:3)+1% methanol) gave the title compound (2.91 g). (¹ H NMR wasconsistent with the desired structure).

Step B:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (2.91 g) in acetonitrile (15 ml) wasadded a solution of 2% hydrogen fluoride in aqueous acetonitrile (2 ml),and the mixture stirred at room temperature. After 4 hours, the solutionwas diluted with ethyl acetate, extracted with saturated sodiumbicarbonate solution and the organic phase dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (1.51g). (¹ H NMR was consistent with the desired structure).

Step C:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1"-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (820 mg in 9 ml 33% methylenechloride in cyclohexane) allyl trichloroacetimidate (366 μl neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (16 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 17 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×15 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ether:hexane (2:3))gave the title compound (800 mg). (¹ H NMR was consistent with thedesired structure).

Step D:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'",3'"-dihydroxypropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (344 mg in 3 ml dry diethyl ether)was added 150 μl pyridine followed by 1.6 ml of a 0.25M osmiumtetraoxide solution in THF and the mixture stirred at room temperature.After 15 minutes, 10 ml of a 20% sodium bisulfite solution were addedand the mixture diluted with 20 ml ethyl acetate. The layers wereseparated and the organic portion re-extracted with 20% sodium bisulfate(3×20 ml) then washed with a saturated brine solution and dried oversodium sulfate. The concentrate was purified by flash chromatography onsilica gel (ethyl acetate:hexane (1:1)+1% methanol, then methylenechloride:hexane:methanol (10:2:1)) to give the title compound (300 mg)(¹ H NMR was consistent with the desired structure).

Step E:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'",3'"-dihydroxypyroploxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (284 mg in 6 ml of in 20% aqueoustetrahydrofuran) was added sodium metaperiodate (72.3 mg) and themixture stirred vigorously for 2 hours. At this time an additional 50 mgof sodium metaperiodate were added. After 1.5 hours the mixture wasdiluted with ethyl acetate and extracted from half-saturated sodiumbicarbonate. The organic portion was dried over magnesium sulfate andpurified by flash chromatography on silica gel (ethyl acetate:hexane(1:1)+1% methanol) to give the title compound (151 mg).(¹ H NMR wasconsistent with the desired structure).

Step F:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsilioxy)-12-[2'-(4"-(2'"-benzylamino)-ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (9.5 mg in 0.25 ml dryterahydrofuran) was added benzylamine (2.5 μl) and the mixture stirredfor 10 minutes at room temperature. This was cooled to -78° C. andacetic acid (10 μl) was added followed by potassium triphenylborohydride(25 μl of a 0.5M solution in THF). After 45 minutes, the reaction wasquenched by the addition of saturated ammonium chloride and warmed toroom temperature. The mixture was extracted with ethyl acetate (3×5 ml)and dried over magnesium sulfate. The concentrate was purified by flashchromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol,then 2% ammonium hydroxide, 5% methanol in methylene chloride) to givethe title compound (3.5 mg).

MASS (FAB) 1039 (M+). (¹ H NMR was consistent with the desiredstructure).

Step G:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-benzyl-amino)-ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (3.5 mg) in acetonitrile (100 μl) wasadded a solution of 2% HF in aqueous acetonitrile (100 μl), and themixture stirred at room temperature. After 2 hours, the solution wasdiluted with ethyl acetate, extracted with saturated sodium bicarbonatesolution and the organic phase dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:1)+1% methanol, then 2% ammonium hydroxide, 5%methanol in methylene chloride) gave the title compound (2 mg).

MASS (FAB) 925 (M+).

Partial ¹ H NMR δ: 7.32 (m, 5H); 5.32M, 5.17m (brd J=3 Hz, 1H); 4.84m,4.21M (brs, 1H); 4.59 (brd, J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 3.84(brs, 2H).

EXAMPLE 7117-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (400 mg in 6 ml 33% methylenechloride in cyclohexane), allyl trichloroacetimidate (209 μl neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (9 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 6 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×10 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:3)+1% methanol) gave the title compound (320 mg). (¹ H NMR wasconsistent with the desired structure).

Step B:17-Ethyl-1-hydroxy-12-[2'-(4"-(2'",3'"-dihydroxypropyloxy)-3"-methoxycyclohexyl)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetrone (310 mg in 3.5 ml dry ether) was added350 μl pyridine followed by 1.5 ml of a 0.25M osmium tetraoxide solutionin THF and the mixture stirred at room temperature. After 15 minutes, 10ml of a 20% sodium bisulfite solution were added and the mixture dilutedwith 20 ml ethyl acetate. The layers were separated and the organicportion re-extracted with 20% sodium bisulfite (3×20 ml) then washedwith a saturated brine solution and dried over sodium sulfate. Theconcentrate was purified by flash chromatography on silica gel (ethylacetate:hexane (1:1)+1% methanol, then methylenechloride:hexane:methanol (10:2:1)) to give the title compound (232 mg).(¹ H NMR was consistent with the desired structure).

Step C:17-Ethyl-1-hydroxy-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-(2'",3'"-dihydroxypropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (232 mg in 25% aqueoustetrahydrofuran) was added sodium metaperiodate (70.2 mg) and themixture stirred vigorously. After 4 hours the mixture was diluted withethyl acetate and extracted from half-saturated sodium bicarbonate. Theorganic portion was dried over magnesium sulfate and purified by flashchromatography on silica gel (ethyl actate:hexane (1:1)+1% methanol) togive the title compound (112 mg). (¹ H NMR was consistent with thedesired structure).

Step D:17-Ethyl-1-hydroxy-12-[2'-(4"-(2'"-benzylamino)-ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (4 mg in 0.30 ml dry terahydrofuran)was added benzylamine (2.0 μl) and the mixture stirred for 10 minutes atroom temperature. This was cooled to -78° C. and acetic acid (7 μl) wasadded followed by potassium triphenylborohydride (16 μl of a 0.5Msolution in THF). After 35 minutes, the reaction was quenched by theaddition of saturated amonium chloride and warmed to room temperature.The mixture was extracted with ethyl acetate (3×5 ml) and dried overmagnesium sulfate. The concentrate was purified by flash chromatographyon silica gel (ethyl acetate:hexane (1:2)+1% methanol, then 2% ammoniumhydroxide, 5% methanol in methylene chloride) to give the title compound(2.1 mg).

Partial ¹ H NMR δ: 7.32 (m, 5H); 4.56 (brd, J=4 Hz, 1H); 4.41 (brd J=14Hz, 1H); 3.82 (brs, 2H).

EXAMPLE 7217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,35-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2-hydroxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tetra-butyldimethylsiloxy)-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (126 mg in 1.3 ml dry terahydrofuran)at -78° C. was added potassium triphenylborohydride (320 μl of a 0.5Msolution in THF). After 45 minutes, the reaction was quenched by theaddition of saturated ammonium chloride and warmed to room temperature.The mixture was extracted with ethyl acetate (3×15 ml) and dried overmagnesium sulfate. The concentrate was purified by flash chromatographyon silica gel (ethyl acetate:hexane (2:1+1% methanol) to give the titlecompound (80.2 mg). (¹ H NMR was consistent with the desired structure).

Step B:17-Ethyl-1-hydroxy-14-(tetra-butyldimethylsiloxy)-12-[2'-(4"-(2-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2-hydroxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (41.7 mg in 0.6 ml 33% methylenechloride in cyclohexane), benzyl trichloroacetimidate (15.8 μl neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 7 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:3)+1% methanol) gave the title compound (24 mg). (¹ H NMR wasconsistent with the desired structure).

Step C:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-benzyl-oxyethoxy-3'-methoxycyclohexyl)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetra-methyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (10 mg) in acetonitrile (500 μl) wasadded a solution of 2% HF in aqueous acetonitrile (200 μl), and themixture stirred at room temperature. After 2.5 hours, the solution wasdiluted with ethyl acetate, extracted with saturated sodium bicarbonatesolution and the organic phase dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (4 mg).

MASS (FAB) 932 (M+Li).

Partial ¹ H NMR δ: 7.33 (m, 5H); 5.32M, 5.19m (brd J=3 Hz, 1H); 4.85m,4.21M (brs, 1H); 4.58 (s, 2H); 4.41 (brd J=14 Hz, 1H).

EXAMPLE 7317-Ethyl-1,14-dihydroxy-12-[2'-(4"-benzyloxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3'-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg in 2 ml methylene chloride)was added disopropylethylamine (99.4 μl) followed by benzyl chloromethylether (34.2 μl neat) and the mixture stirred at room temperature. After24 hours, the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (92mg).

MASS: (FAB) 918 (M+Li).

Partial ¹ H NMR δ: 7.33 (m, 5H); 5.32M, 5.19m (brd J=3 Hz, 1H); 4.87 (s,2H); 4.63 (s, 2H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

EXAMPLE 7417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(napth-2-yloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(napth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone in 33% methylene chloride/cyclohexaneis added 1.5 equivalents of allyl trichloroacetimidate, and the reagentsare allowed to mix for 5 minutes. A catalytic amount oftrifluoromethanesulfonic acid is then added slowly via syringe and themixture is stirred at room temperature. After 3 hours the reaction isquenched by the addition of saturated sodium bicarbonate and extractedwith ethyl acetate. The combined organics are washed with brine anddried over magnesium sulfate. Purification of the concentrate by flashchromatography on silica gel gives the title compound.

EXAMPLE 7517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-t-butyldimethylsiloxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3-10,16-tetraone (700 mg in 12 ml methylenechloride)4-t-butyldimethylsiloxycinnamyl trichloroacetimidate (550 μlneat) was added and the reagents allowed to mix for 5 minutes.Camphorsulfonic acid (35 mg) was added and the mixture stirred at roomtemperature. After 5 hours the reaction was quenched by the addition ofsaturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml).The combined organics were washed with brine and dried over magnesiumsulfate. Purification of the concentrate by flash chromatography onsilica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the titlecompound (190 mg).

¹ H NMR spectrum was consistent with the desired structure.

EXAMPLE 7617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-t-butyldimethylsiloxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (190 mg in 2 ml tetrahydrofurancontained in a polypropylene vial) was added 500 μof a solution ofhydrogen fluoride-pyridine complex (40% in (2:1)tetrahydrofuran:pyridine) and the mixture stirred at room temperature.After 2 hours, the reaction was quenched by the careful addition ofsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organics were dried over magnesium sulfate, concentrated invacuo and purified by flash chromatography on silica gel (ethylacetate:hexane (2:1) to give the title compound (50 mg).

MS(FAB) 930 (M+Li).

¹ H NMR spectrum was consistent with the desired structure.

EXAMPLE 7717-Ethyl-1,14,dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (41 mg in 0.5 ml methylene chloride)at -78° C. was added phenylmagnesium bromide (15 μL of a 3M solution indiethyl ether) and the mixture stirred a low temperature. After 30minutes the reaction was quenched by addition of saturated ammoniumchloride and extracted with ethyl acetate. The organics were dried bypassage through a magnesium sulfate plug and the concetrate purified byflash chromatography on silica gel (ethyl acetate:hexane (1:2)+1%methanol then (1:1+1% methanol) to give title compound (13 mg).

(¹ H NMR consistent with the desired structure)

Step B: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To solution of 17ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'41-phenyl-2'"hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (13 mg in 0.3 mL methylene chloride)was added powdered 4 Å molecular sieves (10 mg), 4-methylmorpholineN-oxide (6.0 mg), tetrapropylammonium perruthenate (1.0 mg) and thereaction stirred at room temperature. After 30 minutes the mixture wasfiltered through a small diatomaceous earth/silica gel plug and thefiltrate concentrated in vacuo. Purification by flash chromatography onsilica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the titlecompound (10 mg).

(¹ H NMR consistant with the desired structure)

Step C:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (10 mg in 0.4 mL tetrahydrofurancontained in a polypropylene vial) was added 20 μL of a solution ofhydrogen fluoride-pyridine complex (40% in (2:1)tetrahydrofuran:pyridine) and the mixture stirred at room temperature.After 96 hours, the readtion was quenched by the careful addition ofsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organics were dried by passage through a magnesium sulfateplug, concentrated in vacuo and purified by flash chromatography (ethylacetate:hexane (1:1)+1% methanol) to give the title compound (5.2 mg).

MASS: (FAB) 917 (M+Li)

partial ¹ H NMR δ: 7.92 (d J=7 Hz, 2H); 7.47 (m, 3H); 5.31 M, 5.17 m(brd J=3 Hz, 1H); 4.81 m, 4.20 M (brs, 1H); 4.41 (brd J=14 Hz, 1H); 3.06(d J=4 Hz, 1H).

EXAMPLE 77B17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19-21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.⁴,9]octacos-18-ene-2,3,10,16-tetraone (400 mg in 3.0 mLN,N-dimethylformamide) was added 2-bromacetophenone (263 mg) followed bypotassium fluoride (25.6 mg) and the mixture heated to 70° C. After 48hours, the mixture was cooled to room temperature, filtered overdiatomaceous earth, diluted with ethyl acetate and washed with saturatedsodium bicarbonate, water, and brine. The combined organics were driedover magnesium sulfate and concentrated in vacuo. Purification by flashchromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol)gave the desired product (145 mg).

(¹ H NMR consistent with the desired structure)

Step B:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Conducted essentially as described in Example 77 Step C to give thedesired product (86 mg).

(¹ H NMR consistent with the desired structure).

EXAMPLE 7817-Ethyl-1,14-dihydroxy-12-[2'-(4"-2'"-(3""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared employing the procedure essentially asdescribed in Example 77, Steps A-C using 3-methoxyphenylmagnesiumbromide as the nucleophile in Step A.

MASS: (FAB) 940 (M+)

partial ¹ H NMR δ: 7.46 (m, 2H); 7.33 (t J=8 Hz, 1H); 7.09 (dd J=8,2 Hz,1H); 5.31M, 5.17 m (brd J=3 Hz, 1H); 4.81m, 4.20M (brs, 1H); 4.41 (brdJ=14 Hz, 1H); 3.84 (s, 3H); 3.07 (d J=Hz, 1H).

EXAMPLE 7917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-hydroxyethyloxy-)3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-1-8-ene-2,3,10,16-tetrone (29 mg in 0.6 mL tetrahydrofurancontained in a polypropylene vial) was added 80 μL of a solution ofhydrogen fluoride-pyridine complex (40% in (2:1)tetrahydrofuran:pyridine) and the mixture stirred at room temperature.After 48 hours, the reaction was quenched by the careful addition ofsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organics were dried by passage through a magnesium sulfateplug, concentrated in vacuo and purified by flash chromatography (ethylacetate:hexane (1:1)+1% methanol) to give the title compound (9.5 mg).

MASS (FAB) 942 (M+)

partial ¹ H NMR δ: 7.23 (m, 1H); 6.94 (s, 1H); 6.91 (d J=8 Hz, 1H); 6.79(d J=8 Hz, 1H); 5.31M, 5.17m (brd J=3 Hz, 1H); 4.41 (brd J=14 Hz, 1H);3.78 (s, 3H); 3.07 (d J=4 Hz, 1H).

EXAMPLE 8017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared employing the procedure essentially asdescribed in Example 77, steps A-C using 4-methoxyphenylmagnesiumbromide as the nucelophile in Step A.

MASS (FAB) 940 (M+)

partial ¹ H NMR δ: 7.92 (d J=9 Hz,2H); 6.91 (d J=9 Hz, 2H); 1H); 5.31M,5.17m (brd J=3 Hz, 1H); 4,81m, 4.20M (brs, 1H); 4.41 (brd J=14 Hz, 1H);3.84 (s, 3H); 3.07 (d J=4 Hz, 1H).

EXAMPLE 8117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-fluorcinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 using m-fluorocinnamyltrichoroacetimidate as the electrophile.

MASS (FAB) 948 (M+Na)

partial ¹ H NMR δ: 7.30-6.85 (m, 4H); 6.59 (d J=17 Hz, 1H); 6.30 (dtJ=17, 6 Hz, 1H); 5.30 M, 5.17 m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H);4.31 (d J=5 Hz, 2H).

EXAMPLE 8217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",5'"-difluorocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 using3,5-difluorocinnamyl trichloroacetimidate as the electrophile.

MASS (FAB) 950 (M+Li)

partial ¹ H NMR δ: 6.92-6.56 (m, 3H); 6.55 (d J=16 Hz, 1H); 6.31 (dtJ=16, 6 Hz, 1H); 5.30 M, 5.17 m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H);4.31 (d J=5 Hz, 2H).

EXAMPLE 8317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-nitrocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(m-nitrocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 70 (Step C) usingm-nitrocinnamyl trichloroacetimidate as the electrophile.

¹ H NMR consistent with the desired structure.

Step B:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-nitrocinnamyloxy)-3"-methxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hyxdroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(m-nitrocinnamyloxy)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (124 mg in 1.5 mL tetrahydrofurancontained in a polypropylene vial) was added 600 μL of a solution ofhydrogen fuoride-pyridine complex (40% in (2:1)tetrahydrofuran:pyridine) and the mixture stirred at room temperature.After 30 hours, the reaction was quenched by the careful addition ofsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organics were dried by passage through a magnesium sulfateplug, concentrated in vacuo and purified by flash chromatography onsilica gel (ethyl acetate:hexane (1:1)+1% methanol) to give the titlecompound (43 mg).

MASS (FAB) 959 (M+Li)

partial ¹ H NMR δ: 8.22 (s, 1H); 8.06 (brd J=8 Hz, 1H); 7.66 (brd J=8Hz, 1H); 7.46 (t J=8 Hz, 1H); 6.69 (d J=16 Hz, 1H); 6.44 (dt J=16, 6 Hz,1H); 5.30 M, 5.17 m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 8417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-phenyl-2-propynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 using 3-phenylpropynyltrichloroacetimidate as the electrophile.

MASS (FAB) 912 (M+Li)

partial ¹ H NMR δ: 7.54-7.28 (m, 5H); 5.30 M, 5.17 m (brd J=3 Hz, 1H);4.41 (d J=14 Hz, 1H).

EXAMPLE 8517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-propenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 using2-phenyl-2-propenyl trichloroacetimidate as the electrophile.

MASS (FAB) 915 (M+Li)

partial ¹ H NMR δ: 7.47 (d J=8 Hz, 2H); 7.26 (m, 3H); 5.49 (s, 1H); 5.37(s, 1H); 5.30 M, 5.17 m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 8617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methyvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

Prepared essentialy as described in Example 83 usingp-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimidate as theelectrophile.

MASS (FAB) 930 (M+Li)

partial ¹ H NMR δ: 7.22 (d J=10 Hz, 2H); 6.76 (d J=10 Hz, 2H); 6.51 (dJ=16 Hz, 1H); 6.11 (dt J=16, 6Hz, 1H); 5.30 M, 5.17 m (brd J=3 Hz, 1H);4.41 (d J=14 Hz, 1H).

EXAMPLE 8717-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-hydroxyphenpropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 83(Step A), 56, 83(Step B)using p-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimidate as theelectrophile.

MASS (FAB) 949 (M+Na)

partial ¹ H NMR δ: 7.04 (d J=9 Hz, 2H); 6.72 (d J=9 Hz, 2H); 5.30 M,5.17 m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 8817-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methyvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 usingm-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimiodate as theelectrophile.

MASS (FAB) 930 (M+Li)

partial ¹ H NMR δ: 7.17-6.63 (m, 5H); 6.52 (d J=16 Hz, 1H); 6.23 (dtJ=16, 6 Hz, 1H); 5.69 (s, 1H); 5.30 M, 5.17 m (brd J=3 Hz, 1H) 4.41 (dJ=14 Hz, 1H).

EXAMPLE 8917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxymethylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(m-hydroxymethylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 70 (Step C) usingm-(tert-butyldimethylsiloxymethyl)-benzyl trichloroacetimidate as theelectrophile.

¹ H NMR consistent with the desired structure.

Step B:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxymethyl)benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(m-tert-butyldimethylsiloxymethyl)-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (19.7 mg) in acetonitrile (0.5 ml)was added a solution of 2% HF in aqueous acetonitrile (40 ml), and themixture stirred at room temperature. After 3.5 hours, the solution wasdiluted with ethyl acetate, extracted with saturated sodium bicarbondatesolution and the organic phase dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (6 mg).

MASS (FAB) 934 (M+Na)

partial ¹ H NMR δ: 7.41-7.22 (m, 4H); 5.30 M, 5.17 m (brd J=3 Hz, 1H);4.41(d J=14 Hz, 1H).

EXAMPLE 9017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxycinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(3",4"-di(tert-butyldimethylsiloxy)-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (8.0 g) in dry methylene chloride(150 mL) was added an excess of 2,6-lutidine (4.8 mL) and the mixturewas stirred at room temperature. After 10 minutes,tert-butyldimethylsilyl trifluoromethanesulfonate (7.57 mL) was addedvia syringe. After 1 hour the reaction mixture was diluted with ethylacetate, extracted from 1N hydrochloric acid, washed with water,saturated sodium bicarbonate, brine, and the organic phase dried overmagnesium sulfate. Removal of the solvent in vacuo gave the titlecompound (crude 12.5 g).

¹ H NMR consistent with the desired structure.

Step B:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(3",4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(3",4"-di(tert-butyldimethylsiloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (11.6 g) in methylene chloride (100mL) was added a methanolic solution of p-toluenesulfonic acid (100 mL ofa 10% solution w/v) and the mixture stirred at room temperature. After30 minutes, the reaction was cooled to 0° C. and quenched by the carefuladdition of saturated sodium bicarbonate solution. The mixture wasextracted with ethyl acetate and the organic portion washed with brine,dried over magnesium sulfate, and the concentrate purified by flashchromatography on silica gel (ethyl acetate:hexane (3:2) to give thetitle compound (8.4 g)

¹ H NMR consistent with the desired structure.

Step C:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-(tert-butyldimethylsiloxy)-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone and

17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19, 21, 27-tetramethyl-11,28-diaoxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tertbutyldimethylsiloxy)-12-[2'-(3",4"-hydroxycylohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (8.17 g) in dry methylene chloride(92 mL) was added an excess of 2,6-lutidine (1.6 mL) and the mixture wasstirred at 0° C. on an ice bath. After 10 minutes,tert-butyldimethylsilyl trifluoromethanesulfonate (2.1 mL) was added viasyringe and the mixture allowed to warm slowly to room temperature.After 1 hour the reation mixture was diluted with ehtyl acetate,extracted from 1N hydrochloric acid, washed with water, saturated sodiumbicarbonate, brine, and the organic phase dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(10% acetone in hexane) gave the title compounds (3"ether: 1.81 g,4"ether: 1.20 g).

¹ H NMR consistent with the desired structure.

Step D:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxycinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 usingm-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimidate as theelectrophile.

MASS (FAB) 916 (M+Li)

partial ¹ H NMR δ: 7.22-6.67 (m, 5H); 6.52 (d J=16 Hz, 1H); 6.23 (dtJ=16, 6 Hz, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14Hz, 1H).

EXAMPLE 9117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",5'"-difluorocinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,-10,16-tetraone

Prepared essentially as described in Example 90 using3,5-difluorocinnamyl trichloroacetimidate as the electrophile.

MASS (FAB) 936 M+Li)

partial ¹ H NMR δ: 6.90-6.58 (m, 3H); 6.51(d J=16 Hz, 1H; 6.38 (dt J=26,6 Hz, 1H); 5.30 M, 5.17 n (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 9217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(p-(tert-butyldimethylsiloxymethyl)-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 usingp-(tert-butyldimethylsiloxymethyl)-benzyl trichloroacetimidate as theelectrophile.

¹ H NMR consistent with the desired structure.

Step B:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(p-hydroxymethyl)-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tertbutyldimethylsiloxy)-12-[2'-(4"-(p-(tert-butyldimethylsiloxymethyl)-benzyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (420 mg) in methylene chloride (10mL) was added a methanolic solution of p-toluenesulfonic acid (10 mL ofa 10% solution w/v) and the mixture stirred at room temperature. After 5minutes, the reaction was cooled to 0° C. and quenched by the carefuladdition of saturated sodium bicarbonate solution. The mixture wasextracted with ethyl acetate and the organic portion washed with brine,dried over magnesium sulfate, and the concentrate purified by flashchromatography on silica gel (ethyl acetate:hexane (1:1+1% methanol) togive the title compound (316 mg).

¹ H NMR consistent with the desired structure.

Step C:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy(-12-[2'-(4"-(p-formylbenzyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.9⁴,9]octacos-18-ene-2,3,10.16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tertbutyldimethylsiloxy)-12-[2'-(4"-(p-hydroxymethyl)-benzyloxy-3"-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (316 mg) in methylene chloride (6.0mL) was added powdered 4 Å molecular sieves (20 mg) followed by4-methylmorpholine-N-oxide (84.5 mg) and tetra-n-propylammoniumperruthenate (5.5 mg), and the mixture stirred at room temperature.After 15 minutes, the mixture was filtered through a small silica gelcolumn, washed with ethyl acetate, and the concentrated organicspurified by flash chromatography on silica gel (ethyl acetate:hexane(1:1)+1% methanol) to give the title compound (282 mg).

¹ H NMR consistent with the desired structure.

Step D:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(p-carboxybenzyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-end-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy-12-[2'-(4"-(p-formylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (50 mg) in tert-butanol (1.0 mL) wasadded 2- methyl-2-butene (250 mL) followed by 0.5 mL of an aqueoussolution of sodium chlorite (41 mg) and sodium dihydrogen phosphate (48mg), and the mixture stirred at room temperature. After 1.5 hours, themixture was concentrated and redissolved in ethyl acetate:hexane (1:1)and washed with water. The organic portion as dried over sodium sulfate,and the concentrate purified by flash chromatography on silica gel(ethyl acetate:hexane (4:1)+1% methanol+0.5% acetic acid) to give thetitle compound (43 mg).

¹ H NMR consistent with the desired structure.

Step E:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(p-carboxybenzyloxy)-3"-methoxycyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 89 (Step B)

MASS (FAB) 933 (M+Li)

partial ¹ H NMR δ: 8.04 (d J=8 Hz, 2H); 7.44 (d J=8 Hz, 2H; 5.30 M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H); 4.73 (s, 2H).

EXAMPLE 9317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carboxylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 92 usingm-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimidate as theelectrophile.

MASS (FAB) 949 (M+Na)

partial ¹ H NMR δ: 8.07 (s, 1H); 7.97 (d J=8 Hz, 1H); 7.60 (d J=8 Hz,1H); 7.41 (t J=8 Hz, 1H); 5.30 M, 5.17 m (brd J=3 Hz, 1H); 4.41 (d J=14Hz, 1H).

EXAMPLE 9417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carbomethoxybenzyloxy)-3"-methoxcyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone (7 mg) in methylene chloride:methanol(2:1, 0.75 mL) at 0° C. was added a methylene chloride solution oftrimethylsilyldiazomethane (10% by weight) until a yellow coloredpersisted. The mixture was then warmed to room temperature, concentratedin vacuo, and purified by flash chromatography on silica gel(acetone:hexane (1:2)) to give the title compound (5.5 mg).

MASS (FAB) 963 (M+Na)

partial ¹ H NMRδ: 8.03 (d J=8 Hz, 2H); 7.46 (d J=8 Hz, 2H); 5.30 M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H); 3.92 (s, 3H).

EXAMPLE 9517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-isopropylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-(12-[2'-(4"-(m-isopropylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tertbutyldimethylsiloxy)-12-[2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone (50 mg) in methylene chloride (1.0mL) was added 4-benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP, 32 mg) followed by triethylamine (14μL) andthe mixture stirred at room temperature. After 10 minutes,isopropylamine (8.0 μL) was added, and the reaction stirred at roomtemperature for 12 hours. At this time the mixture was concentrated andpurified by flash chromatography on silica gel (ethyl acetate:hexane(1:1)+1% methanol) to give the title compound (43 mg).

¹ H NMR consistent with the desired structure.

Step B:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(m-isopropylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 89 (Step B).

MASS (FAB) 974 (M+Li)

partial ¹ H NMR δ: 7.81 (s, 1H); 7.69 (d J=7 Hz, 1H); 7.44 (m, 2H); 6.00(d J=8 Hz, 1H); 4.75 (s, 2H); 5.30 M, 5.17 m (brd J=3 Hz, 1H); 4.41 (dJ=14 Hz, 1H).

EXAMPLE 9617-Ethyl-1,14-dihydroxy-12-[2'-(4"-m-butylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 95 (Step A), 83 (Step B)using n-butyl amine as the nucleophile.

MASS (FAB) 988 M+Li)

partial ¹ H NMR δ: 7.82 (s, 1H; 7.70 (d J=7 Hz, 1H); 7.44 (m, 2H); 6.18(t J=5 Hz, 1H); 5.30 M, 5.17 m (brd J=3 Hz), 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 9817-Ethyl-1,14-dihydroxy-12-[2'-(4"-acetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butylidimethylsiloxy)-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone (311 mg) in tert-butanol (6.6 ml) and2-methyl-2-butene (1.65 ml) was added sodium chlorite (273 mg) andsodium dihydrogen phosphate (272 mg) in water (2.7 ml) slowly. After 2hours, the solvent was removed in vacuo, and the resulting residue wasdissolved in water and acidified to pH 3 with 1N HCl. The aqueous layerwas extracted with ethyl acetate (3×10 ml), and the combined organicportions washed with brine, dried over magenesium sulfate and purifiedby flash chromatography on silica gel (2% methanol in methylene chloridefollowed by 2% methanol in methylene chloride+0.5% acetic acid) to givethe title compound (255 mg).

¹ H NMR consistent with the desired structure.

Step B:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-acetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (24.3 mg) in methylenechloride:N,N-dimethylformamide (4:1, 0.5 mL) was added an admixture of1-hydroxybenzotriazole hydrate (4.0 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.7 mg) andthe mixture atirred at room temperature. After 30 minutes, ammoniumhydroxide (4.0 μL of a 25% aqueous solution) was added and the mixturestirred for an additional 4 hours. At this time, the solution wasfiltered over diatomaceous earth, diluted with ethyl acetate, andextracted with sodium bicarbonate. The organic portion was dried overmagnesium sulfate, concentrated in vacuo, and purified by flashchromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol,then (2:1)+1% methanol) to give the title compound (14 mg).

¹ H NMR consistent with the desired structure.

Step C:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-acetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 (Step B).

MASS (FAB) 872 (M+Na)

partial ¹ H NMR δ: 7.79 (s, 2H); 5.30 M, 5.17 m (brd J=3 Hz, 1H); 4.41(d J=14 Hz, 1H).

EXAMPLE 9817-Ethyl-1,14-dihydroxy-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 89 (Step B).

MASS (FAB) 863 (M+2Li)

partial ¹ H NMR δ: 5.24 (m, 2H); 5.02 (brd J=9 Hz), 1H); 4.94 (m, 1H);4.44 (m, 2H).

EXAMPLE 9917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(N-phenylacetamidoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 95 (Step A) from17-ethyl-1,14-dihydroxy-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone using aniline as the nucleophile.

MASS (FAB) 932 (M+Li)

partial ¹ H NMR δ: 9.57 (brs, 1H); 7.61-7.05 (m, 5H); 5.26 (m, 2H); 4.42(m, 2H).

EXAMPLE 10017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(N-benzylacetamidoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 97 (Step B) from17-ethyl-1,14-dihydroxy-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone using benzylamine as the nucleophile.

MASS (FAB) 946 (M+Li)

partial ¹ H NMR δ: 8.14 (brs, 1H); 7.30 (m, 5H); 5.21 (m, 2H); 3.04 (s,2H).

EXAMPLE 10117-Ethyl-1-hydroxy-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 97 (Step A) from17-ethyl-1-hydroxy-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

¹ H NMR consistent with the desired structure.

EXAMPLE 10217-Ethyl-1-hydroxy-12-[2'-(4"-(N-benzylamidoxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 95 (Step A) usingbenzylamine as the nucleophile.

MASS (FAB) 930 (M+Li)

partial ¹ H NMR δ: 8.19 (brs, 1H); 7.29 (m, 5H); 4.85 (brd J=8 Hz, 1H);4.55 (m, 2H).

EXAMPLE 10317-Ethyl-1-hydroxy-12-[2'-(4"-(N-methyltyrosine)amidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 95 (Step A) using tyrosinemethyl ester hydrochloride as the nucleophile.

MASS (FAB) 1018 (M+Li)

partial ¹ H NMR δ: 6.98 (m, 2H); 6.73 (m, 2H); 4.02 (m, 2H); 3.69 (s,3H).

EXAMPLE 10417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(m-methylphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 77 using m-methylphenylmagnesium bromide as the nucleophile.

MASS (FAB) 931 (M+Li)

partial ¹ H NMR δ: 7.70 (m, 2H); 7.32 (m, 2H); 5.30 M, 5.17 m (brd J=3Hz, 1H); 4.41 (d J=14 Hz, 1H); 2.39 (s, 3H).

EXAMPLE 10517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-p-methylphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 77 using p-methylphenylmagnesium bromide as the nucleophile.

partial ¹ H NMR δ: 7.82 (d J=8 Hz, 2H); 7.23 (d J=8 Hz, 2H); 5.30 M,5.17 m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz), 1H); 2.33 (s, 3H).

EXAMPLE 10617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 77 (Steps A,C) using phenylmagnesium bromide as the nucleophile.

MASS (FAB) 919 (M+Li)

partial ¹ H NMR δ: 7.32 (m, 5H); 5.30 M, 5.17 m (brd J=3 Hz, 1H); 4.41(d J=14 Hz, 1H); 3.08 (d J=3 Hz, 1H).

EXAMPLE 10717-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(m-methylphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 77 (Steps A,C) usingm-methylphenyl magnesium bromide as the nucleophile.

MASS (FAB) 933 (M+Li)

partial ¹ H NMR δ: 7.25-7.03 (m, 4H); 5.30 M, 5.17 m (brd J=3 Hz, 1H);4.41 (d J=14 Hz, 1H); 2.32 (s, 3H).

EXAMPLE 10817-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-m-ethylphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 77 (Step A), 56, 77 (StepsB,C) using m-vinylphenyl magnesium bromide as the nucleophile.

MASS (FAB) 945 (M+Li)

partial ¹ H NMR δ: 7.75 (s, 1H); 7.71 (d J=6 Hz, 1H); 7.37 (m, 2H); 5.30M, 5.17 m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H); 2.68 (q J=8 Hz, 2H);1.22 (t J=8 Hz, 3H).

EXAMPLE 10917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenylethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-phenyl-2'"-trifluoroacetoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (23.3 mg) in methylene chloride (0.6mL) was added triethylamine (12 μL) followed by trifluoroaceticanhydride (6.4 μL) and N,N-dimethylaminopyridine (3 mg) and the mixturestirred at room temperature. After 15 minutes, the reaction was quenchedby the addition of saturated sodium bicarbonate solution, extracted withethyl acetate, and the organics dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:3)+1% methanol) gave the title compound (5 mg).

¹ H NMR consistent with the desired structure.

Step B:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenylethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 56 and 83 (Step B).

MASS (FAB) 919 (M+Na)

partial ¹ H NMR δ: 7.30-7.22 (m, 5H); 5.30 M 5.17 m (brd J=3 Hz, 1H);4.41 (d J=14 Hz, 1H).

EXAMPLE 11017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-acetoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 104 (Step A) and 83 (StepB) using acetic anhydride as the electrophile.

partial ¹ H NMR δ: 7.33 (m, 5H); 6.03 (m, 1H); 5.30 M, 5.17 m (brd J=3Hz, 1H); 4.41 (d J=14 Hz, 1H); 2.09 (s, 3H).

EXAMPLE 11117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-morpholinoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-methanesulfonyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (80.8 mg) in methylene chloride (1.0mL) was added triethylamine (23 μL) followed by methanesulfonyl chloride(7.2 μL) and the mixture stirred at room temperature. After 10 minutes,the reaction was quenched by the addition of saturated sodiumbicarbonate solution, extracted with ethyl acetate, and the organicportion dried over magnesium sulfate. Purification of the concentrate byflash chromatography on silica gel (ethyl acetate:hexane (2:1)+1%methanol) gave the title compound (74 mg).

¹ H NMR consistent with the desired structure.

Step B:17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-morpholinoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-methanesulfonyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (26.5 mg) in dry tetrahydrofuran (0.3mL) was added 200 μL of a sodium morpholine solution (prepared byaddition of 10 μL morpholine to a suspension of 2.3 mg sodium hydride in0.5 mL of tetrahydrofuran) and the mixture heated to 70° C. After 6hours, the mixture is cooled to room temperature and quenched by theaddition of saturated ammonium chloride solutin, extracted with ethylacetate, and the organic portion dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (2:1)+1% methanol, then 2% ammonium hydroxide, 5%methanol, in methylene chloride) gave the title compound (10 mg).

¹ H NMR consistent with the desired structure.

Step C:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-morpholinoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 (Step B).

MASS (FAB) 911 (M+Li)

partial ¹ H NMR δ: 5.30 M, 5.17 m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz,1H); 3.71 (m, 4H); 2.56 (m, 4H).

EXAMPLE 11217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-ylmethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 using naphth-2-ylmethyltrichloroacetimidate as the electrophile and diethyl ether as thesolvent. MASS (FAB) 938 (M+Li)

¹ H NMR consistent with the desired structure.

EXAMPLE 11317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'",5'"-methylenedioxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 using4,5-methylenedioxybenzyl trichloroacetimidate as the electrophile.

MASS (FAB) 932 (M+Li)

partial ¹ H NMR δ: 6.88 (s, 1H); 6.78 (d J=7 Hz, 1H); 6.74 (d J=7 Hz,1H); 5.92 (s, 2H); 4.59 (d J=8 Hz, 1H); 4.52 (d J=8 Hz, 1H).

EXAMPLE 11417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-N,N,-dimethylaminophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtri(p-N,N-dimethylphenyl) bismuth diacetate as the arylating agent.

MASS (FAB) 917 (M+Li)

partial ¹ H NMR δ: 6.87 (d J=10 Hz, 2H); 6.68 (d J=10 Hz, 2H); 2.83 (s,6H).

EXAMPLE 11517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 using tri(m-fluorophenyl)bismuth diacetate as the arylating agent.

MASS (FAB) 892 (M+Li)

¹ H NMR consistent with the desired structure.

EXAMPLE 11617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-(2""-dioxolanylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtris(3-(2'-dioxolanyl)phneyl) bismuth diacetate as the arylating agent.

MASS (FAB) 946 (M+Li)

partial ¹ H NMR δ: 7.3-6.9 (m, 4H); 5.78 (s, 1H); 4.13-3.97 (m, 4H).

EXAMPLE 117

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-formylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 90 (Step B) from17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-(2""-dioxolanylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

MASS (FAB) 902 (M+Li)

¹ H NMR consistent with the desired structure.

EXAMPLE 11817-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-carboxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 92 (Step D) from17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-formylphenyloxy)-3"-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

¹ H NMR consistent with the desired structure.

EXAMPLE 11917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dimethoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtris(3,4-dimethoxyphenyl) bismuth acetate as the alkylating agent.

MASS (FAB) 934 (M+Li).

partial ¹ H NMR δ: 6.72 (d J=8 Hz., 1H); 6.56 (d J=2.5 Hz, 1H); 6.47 (ddJ=8, 2.5 Hz, 1H); 4.57 (brd J=8 Hz, 1H); 4.39 (brd J=14.5 Hz, 1H); 3.79(s, 3H); 3.77 (s, 3H).

EXAMPLE 12017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-trifluoromethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtris(4-fluoromethylphenyl) bismuth acetate as the alkylating agent.

MASS (FAB) 942 (M+Li).

partial ¹ H NMR δ: 7.48 (d J=9.5 Hz, 2H); 6.98 (d J=9.5 Hz, 2H); 4.59(brd J=5 Hz, 1H); 4.41 (brd, J=14.5 Hz, 1H).

EXAMPLE 12117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",5'"-bis(trifluoromethyl)phenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtris(3,5-bis(trifluoromethyl)phenyl) bismuth acetate as the alkylatingagent.

MASS (FAB) 1010 (M+Li).

partial ¹ H NMR δ: 7.39 (s, 1H); 7.34 (s, 2H); 4.59 (brd J=5 Hz, 1H);14.4 (brd J=14.5 Hz, 1H).

EXAMPLE 12217-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-methylphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethy-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 2 from17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]octacos- 18-ene-2,3,10,16-tetraone using tri-(p-methylphenyl) bismuthdiacetate as the alkylating agent.

A. (4"-ether):

partial ¹ H NMR δ: 7.07 (d J=8.4 Hz, 2H); 6.83 (d J=8.4 Hz, 2H); 5.2-4.8(m, 3H); 4.75 (s, 1H).

B. (3"-ether): MASS (FAB) 859 (M+Li)

partial ¹ H NMR δ: 7.07 (d J=8.4 Hz, 2H); 6.82 (d J=8.4 Hz, 2H);5.15-4.8 (m, 3H)

EXAMPLE 123 A.17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-hydroxyphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 122 and 90 (Step B) usingtris-(p-(tert-butyldimethylsiloxy)phenyl) bismuth diacetate as thealkylating agent.

A. (4"-ether): MASS (FAB) 862 (M+Li)

partial ¹ H NMR d: 6.80 (d J=9 Hz, 2H); 6.72 (d J=9 Hz, 2H); 5.24 (brs,1H); 5.1-4.8(m, 3H).

B. (3"-ether): MASS (FAB) 962 (M+Li)

partial ¹ H NMR δ: 6.80 (d J=9 Hz, 2H); 6.72 (d J=9 Hz, 2H); 5.37 (brs,1H); 5.1-4.9 (m, 3H).

EXAMPLE 124 A.17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-hyroxymethylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-hydroxymethylphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared esssentially as described in Examples 122 and 90 (Step B) usingtris-(p-(tert-butyldimethylsiloxymethyl)phenyl) bismuth diacetate as thealkylating agent.

A. (4"-ether): MASS (FAB) 875 (M+Li)

partial ¹ H NMR δ: 7.26 (d J=10.2 Hz, 2H); 6.90 (d J=10.2 Hz, 2H);5.1-4.8 (m, 3H); 4.59 (s, 2H).

B. (3"-ether): MASS (FAB) 875 (M+Li)

partial ¹ H NMR δ: 7.26 (d J=9.75 Hz, 2H); 6.91 (d J=9.75 Hz, 2H);5.1-4.8 (m, 3H); 4.59 (brs, 2H).

EXAMPLE 12517-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-formylphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 92 (Step C) from17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-hydroxymethylphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

partial ¹ H NMR δ: 9.80 (s, 1H); 7.83 (d J=8.5 Hz, 2H); 7.01 (d J=8.5Hz, 2H); 5.20-4.95 (m, 2H); 4.87 (d J=9.4 Hz, 1H).

EXAMPLE 126 A.17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-N,N-dimethylaminophenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-N,N-dimethylaminophenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 122 usingtri-(p-N,N-dimethylaminophenyl) bismuth diacetate as the alkylatingagent.

A. (4"-ether):

partial ¹ H NMR δ: 6.86 (d J=9.06 Hz, 2H); 6.68 (d J=9.06 Hz, 2H);5.15-4.80 (m, 3H).

B. (3"-ether):

partial ¹ H NMR δ: 6.87 (d J=7.3 Hz, 2H); 6.68 (d J=7.3 Hz, 2H);5.1-4.80 (m, 3H).

EXAMPLE 127 A.17-Ethyl-1-hydroxy-12-[2'-(4"-phenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-phenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 122 using tris-(phenyl)bismuth diacetate as the alkylating agent.

A. (4"-ether): MASS (FAB) 860 (M+Na)

partial ¹ H NMR d: 7.25 (m, 2H); 6.92 (m, 3H); 5.10M, 4.85m (t J=9 Hz,2H); 5.00 (m, 2H).

B. (3"-ether): MASS (FAB) 860 (M+Na)

partial ¹ H NMR δ: 7.25 (m, 2H); 6.93 (m, 3H); 5.07 (t J=9 Hz, 2H); 4.97(m, 2H); 4.82 (m, 2H); 4.52 (d J=5 Hz, 2H).

EXAMPLE 128 A.17-Ethyl-1-hydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-methoxyphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 122 usingtris-(p-methoxyphenyl) bismuth diacetate as the alkylating agent.

A. (4"-ether): MASS (FAB) 875 (M+Li)

B. (3"-ether): MASS (FAB) 875 (M+Li)

partial ¹ H NMR δ: 6.87 (m, 2H); 6.78 (m, 2H); 5.05 (t J=9 Hz, 2H); 3.72(s, 3H).

EXAMPLE 129 A.17-Ethyl-1-hydroxy-12-[2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and B.17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(3'"-methoxyphenyloxy)cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 122 usingtris-(m-methoxyphenyl) bismuth diacetate as the alkylating agent.

A. (4"-ether): MASS (FAB) 875 (M+Li)

partial ¹ H NMR δ: 7.13 (t J=10 Hz, 1H); 6.51 (m, 3H); 5.00 (m, 4H);3.72 (s, 3H).

B. (3"-ether): MASS (FAB) 875 (M+Li)

partial ¹ H NMR δ: 7.14 (t J=10 Hz, 1H); 6.49 (t J=10 Hz, 3H); 4.52 (dJ=5 Hz, 1H); 4.38 m, 4.32 M (s, 1H); 3.75 (s, 3H).

EXAMPLES 130-161

Utilizing the general procedures described in Examples 1 to 129, thefollowing compounds of Formula I (wherein R⁴ is hydrogen, R⁵ is methyl,ethyl, propyl or allyl and n is 2) are prepared from the appropriatelysubstituted starting materials and reagents.

    __________________________________________________________________________    EXAMPLE NO.                                                                            R.sup.1            R.sup.2  R.sup.3                                                                          R.sup.5                               __________________________________________________________________________    130                                                                                     ##STR15##         CH.sub.3 H  CH.sub.3 CH.sub.2                     131                                                                                     ##STR16##         CH.sub.2CHCH.sub.2                                                                     OH CH.sub.3 CH.sub.2                     132                                                                                     ##STR17##         CH.sub.3 OH CH.sub.2CHCH.sub.2                    133                                                                                     ##STR18##         CH.sub.3 OH CH.sub.3 CH.sub.2 CH.sub.2            134                                                                                     ##STR19##         CH.sub.3 OH CH.sub.3 CH.sub.2                     135                                                                                     ##STR20##         CH.sub.3 OH CH.sub.3 CH.sub.2                     136                                                                                     ##STR21##         CH.sub.3 OH CH.sub.3 CH.sub.2 CH.sub.2            137                                                                                     ##STR22##         CH.sub.3 H  CH.sub.2CHCH.sub.2                    138                                                                                     ##STR23##         CH.sub.2CHCH.sub.2                                                                     OH CH.sub.3 CH.sub.2                     139                                                                                     ##STR24##         CH.sub.3 OH CH.sub.3 CH.sub.2                     140                                                                                     ##STR25##         CH.sub.3 OH CH.sub.3 CH.sub.2                     141                                                                                     ##STR26##         CH.sub.3 OH CH.sub.3 CH.sub.2                     142                                                                                     ##STR27##         CH.sub.3 OH CH.sub.3 CH.sub.2                     143                                                                                     ##STR28##         CH.sub.3 OH CH.sub.3 CH.sub.2                     144                                                                                     ##STR29##         CH.sub.3 H  CH.sub.2CHCH.sub.2                    145                                                                                     ##STR30##         CH.sub.3 OH CH.sub.3 CH.sub.2                     146                                                                                     ##STR31##         CH.sub.3 OH CH.sub.3 CH.sub.2                     147                                                                                     ##STR32##         CH.sub.3 OH CH.sub.3 CH.sub.2                     148                                                                                     ##STR33##         CH.sub.3 OH CH.sub.3                              149                                                                                     ##STR34##         CH.sub.3 OH CH.sub.3 CH.sub.2                     150                                                                                     ##STR35##         CH.sub.3 OH CH.sub.3 CH.sub.2                     151                                                                                     ##STR36##         CH.sub.3 OH CH.sub.3 CH.sub.2                     152                                                                                     ##STR37##         CH.sub.3 H  CH.sub.3 CH.sub.2                     153                                                                                     ##STR38##         CH.sub.3 H  CH.sub.3 CH.sub.2                     154                                                                                     ##STR39##         CH.sub.3 CH.sub.2                                                                      OH CH.sub.3 CH.sub.2                     155                                                                                     ##STR40##         (CH.sub.3).sub.2 CH                                                                    OH CH.sub.3 CH.sub.2                     156                                                                                     ##STR41##         CH.sub.3 CH.sub.2                                                                      OH CH.sub.3 CH.sub.2                     157                                                                                     ##STR42##         CH.sub.3 CH.sub.2                                                                      OH CH.sub.3 CH.sub.2                     158                                                                                     ##STR43##         CH.sub.3 CH.sub.2 CH.sub.2                                                             OH CH.sub.3 CH.sub.2                     159                                                                                     ##STR44##         CH.sub.3 CH.sub.2 CH.sub.2                                                             OH CH.sub.3 CH.sub.2                     160                                                                                     ##STR45##         CH.sub.3 CH.sub.2 CH.sub.2                                                             OH CH.sub.3 CH.sub.2                     161                                                                                     ##STR46##         (CH.sub.3).sub.2 CH                                                                    OH CH.sub.3 CH.sub.2                     162                                                                                     ##STR47##         (CH.sub.3).sub.2 CH                                                                    OH CH.sub.3 CH.sub.2                     163      H.sub.2 NCH.sub.2 CH.sub.2                                                                       CH.sub.3 OH CH.sub.3 CH.sub.2                     164      H.sub.2 NCH.sub.2 CH.sub.2                                                                       CH.sub.3 H  CH.sub.3 CH.sub.2                     165      (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                              CH.sub.3 OH CH.sub.3 CH.sub.2                     166      (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                              CH.sub.3 H  CH.sub.3 CH.sub.2                     167      CH.sub.3 NHCH.sub.2 CH.sub.2                                                                     CH.sub.3 OH CH.sub.3 CH.sub.2                     168      CH.sub.3 NHCH.sub.2 CH.sub.2                                                                     CH.sub.3 H  CH.sub.3 CH.sub.2                     __________________________________________________________________________

EXAMPLE 120 T-Cell Proliferation Assay

1. Sample Preparation

The compounds to be assayed were dissolved in absolute ethanol at 1mg/ml.

2. Assay

Spleens from C57B1/6 mice were taken under sterile conditions and gentlydissociated in ice-cold RPMI 1640 culture medium (GIBC), Grand Island,N.Y.) supplemented with 10% heat-inactivated fetal calf serum (GIBO)).Cells were pelleted by centrifugation at 1500 rpm for 8 minutes.Contaminating red cells were removed by treating the pellet withammonium chloride lysing buffer (GIBO)) for 2 minutes at 4° C. Coldmedium was added and cells were again centrifuged at 1500 rpm for 8minutes. T lymphocytes were then isolated by separation of the cellsuspension on nylon wool columns as follows: Nylon wool columns wereprepared by packing approximately 4 grams of washed and dried nylon woolinto 20 ml plastic syringes. The columns were sterilized by autoclavingat 25° F. for 30 minutes. Nylon wool columns were wetted with warm (37°C.) culture medium and rinsed with the same medium. Washed spleen cellsresuspended in warm medium were slowly applied to the nylon wool. Thecolumns were then incubated in an upright position at 37° C. for 1 hour.Non-adherent T lymphocytes were eluted from the columns with warmculture medium and the cell suspensions were spun as above.

Purified T lymphocytes were resuspended at 2.5×10⁵ cells/ml in completeculture medium composed of RPMI 1640 medium with 10% heat-inactivatedfetal calf serum, 100 mM glutamine, 1 mM sodium pyruvate, 2×10⁵ M2-mercaptoethanol and 50 μg/ml gentamycin. Ionomycin was added at 250ng/ml and PMA at 10 ng/ml. The cell suspension was immediatelydistributed into 96 well flat-bottom microculture plates (Costar) at 200μl/well. The various dilustions of the compound to be tested were thenadded in triplicate wells at 20 μl/well. The compound17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone was used as a standard. The cultureplates were then incubated at 37° C. in a humidified atmosphere of 5%CO₂ -95% air for 44 hours. The proliferation of T lymphocytes wasassessed by measurement of tritiated thymidine incorporation. After 44hours of culturing, the cells were pulse-labelled with 2 μCi/well oftritiated thymidine (NEN, Cambridge, Mass.). After another 4 hours ofincubation, cultures were harvested on glass fiber filters using amultiple sample harvester. Radioactivity of filter discs correspondingto individual wells was measured by standard liquid scintillationcounting methods (Betacounter). Mean counts per minute of replicatewells were calculated and the results expressed as concentration ofcompound required to inhibit tritiated thymidine uptake of T-cells by50%

A selection of compounds were tested according to the previousprocedure. The title compounds of the following Examples had activity ininhibiting the proliferation of T-cells in the aforementioned assay:

1, 2A, 2B, 3, 4, 5, 6A, 6B, 7, 8A, 8B, 9, 10A, 10B, 11, 12A, 12B, 13,14, 15A, 15B, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 43, 44, 45,46A, 46B, 47B, 48A, 49A, 49B, 50A, 50B, 51A, 51B, 52, 53, 54A, 54B, 55,56, 57, 58, 59, 60, 61, 64, 70, 73, 76, 77, 77B, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,115, 116, 117, 118, 119, 120, 121, 122A, 122B, 123A, 123B, 124A, 124B,125, 126A, 126B, 127A, 127B, 128A, 128B, 129A, and 129 B.

The results of this assay are representative of the intrinsicimmunosuppressive activity of the compounds of the present invention.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe casual variation, adaptations, modifications, deletions, oradditions of procedures and protocols described herein, as come withinthe scope of the following claims and its equivalents.

What is claimed is:
 1. A compound of formula I: ##STR48## or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² are independently selected from(1) hydrogen; (2) phenyl; (3) substituted phenyl in which the substituents are X, Y and Z; (4) 1- or 2- naphthyl; (5) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z; (6) biphenyl; (7) substituted biphenyl in which the substituents are X, Y and Z; (8) C₁₋₁₀ alkyl; (9) substituted C₁₋₁₀ alkyl in which one or more substituents(s) is (are) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ -alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C₁₋₆ alkyl, (g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from(i) hydrogen, (ii) C₁₋₁₀ alkyl unsubstituted for substituted with one or more of the substituent(s) selected from:(a') phenyl, which is unsubstituted or substituted with X, Y and Z, (b') --OH, (c') C₁₋₆ alkoxy, (d') --CO₂ H, (e') --CO₂ --C₁₋₆ alkyl, (f') --C₃₋₇ cycloalkyl, and (f') --OR¹¹, (iii) C₃₋₁₀ alkenyl unsubstituted or substituted with one or more of the substituent(s) selected from:(a') phenyl, which is unsubstituted or substituted with X, Y and Z, (b') --OH (c') C₁₋₆ alkoxy, (d') --CO₂ H, (e') --CO₂ --C₁₋₆ alkyl, (f') --C₃₋₇ cycloalkyl, and (g') --OR¹¹, (iv) or where R⁶ and R⁷ and the N to which they are attached can form a 3-7-membered saturated heterocyclic ring, unsubstituted or substituted with C₁₋₆ alkyl or phenyl, the ring being selected from the group consisting of: aziridine, morpholine, thiomorpholine, thiomorpholine-oxide, thiomorpholine-dioxide, piperidine, pyrrolidine, and piperizine, (h) --NR⁶ CO--C₁₋₆ alkyl--R⁷, wherein R⁶ is as defined above, (i) --NR⁶ CO₂ --C₁₋₆ alkyl--R⁷, (j) --NR⁶ CONR⁶ R⁷, (k) --OCONR⁶ R⁷, (l) --COOR⁶, (m) --CHO, (n) phenyl, (o) substituted phenyl in which the substituents are X, Y and Z, (p) phenyloxy, (q) substituted phenyloxy in which the substituents are X, Y and Z, (r) 1- or 2- naphthyl, (s) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z, (t) biphenyl (u) substituted biphenyl in which the substituents are X, Y and Z; (v) --OR¹¹, and (w) --S(O)_(p) --C₁₋₆ alkyl; (10) C₃₋₁₀ alkenyl; (11) substituted C₃₋₁₀ alkenyl in which one or more substituent(s) is(are) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C₁₋₆ alkyl, (g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above (h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above, (i) --COOR⁶, wherein R⁶ is as defined above, (j) --CHO, (k) phenyl, (l) substituted phenyl in which the substients are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, (q) --OR¹¹, and (r) --S(O)_(p) --C₁₋₆ alkyl; (12) C₃₋₁₀ alkynyl; (13) substituted C₃₋₁₀ alkynyl in which one or more substituent(s) is(are) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents onphenyl are X, Y and Z, (f) --OCO--C₁₋₆ alkyl, (g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, (h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above, (i) --COOR⁶, wherein R⁶ is as defined above, (j) --CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, and (q) --OR¹¹ ; with the proviso that R¹ and R² are not simultaneously hydrogen, methyl or combinations thereof and the further proviso that R¹ is not benzyl; R³ is hydrogen, hydroxy, --OR¹¹ or C₁₋₆ alkoxy; R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond; R⁵ is methyl, ethyl, propyl or allyl; R¹¹ is selected from:(a) --PO(OH)O⁻ M⁺, whereim M⁺ is a positively charged inorganic or organic counterion, selected from the group consisting of: ammonium, sodium, lithium, postassium, calcium, magnesium, dicyclohexylamine, N-methyl-D-glucamine, arginine and lysine, (b) --SO₃ ⁻ M⁺, (c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and (d) --CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from:(i) hydroxy, (ii) C₁₋₆ alkoxy, (iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:(a') hydrogen, and (b') C₁₋₆ alkyl, (iv) --COOR⁶, wherein R⁶ is as defined above, (v) phenyl, (vi) substituted phenyl in which the substituents are X, Y and Z, (vii) --SH, and (viii) --S--C₁₋₆ alkyl; W is O or (H, OH); X, Y and Z independently are selected from:(a) hydrogen, (b) c₁₋₇ alkyl, (c) C₂₋₆ alkenyl, (d) halogen, (e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, and m is 0 to 2, (f) --CN, (g) --CHO, (h) --CF₃, (i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, or phenyl, (j) --SOR⁸, wherein R⁸ is as defined above, (k) --SO₂ R⁸, wherein R⁸ is as defined above, (l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, (m) R⁹ O(CH₂)_(m) -- wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃ alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above, (n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or taken together form an ethyl or propyl bridge, (o) ##STR49## wherein R⁹ and m are as defined above, and (p) ##STR50## wherein R⁹ and m are as defined above, and (q) --OR¹¹ ; or any two of adjacent X, Y and Z can be joined to form a ring selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and n is 1 or
 2. 2. The compound of claim 1 wherein the absolute configuration of formula I is as defined in formula III: ##STR51##
 3. The compound of claim 1 wherein:R¹ and R² are independently selected from:(1) hydrogen; (2) methyl; (3) phenyl; (4) substituted phenyl in which the substituents are X, Y and Z; (5) 1- or 2- naphthyl; (6) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z; (7) biphenyl; and (8) substituted and biphenyl in which the substituents are X, Y and Z; with the proviso that R¹ and R² are not simultaneously hydrogen, methyl or combinations thereof; R³ is hydrogen, hydroxy, or C₁₋₆ alkoxy; R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond; R⁵ is methyl, ethyl, propyl or allyl; R¹¹ is selected from:(a) --PO(OH)O⁻ M⁺, wherein M⁺ is a positively charged inorganic or organic counterion, selected from the group consisting of: ammonium, sodium, lithium, potassium, calcium, magnesium, dicyclohexylamine, N-methyl-D-glucamine, arginine and lysine, (b) --SO₃ ⁻ M⁺, (c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and (d) --CO--C₁₋₆ alkyl--NR⁶ R⁷, wherein R⁶ and R⁷ are as defined below and the alkyl is unsubstituted or substituted with one or more substituents selected from:(i) hydroxy, (ii) C₁₋₆ alkoxy, (iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:(a') hydrogen, and (b') C₁₋₆ alkyl, (iv) --COOR⁶, wherein R⁶ is as defined below, (v) phenyl, (vi) substituted phenyl in which the substituents are X, Y and Z, (vii) --SH, and (viii) --S--C₁₋₆ alkyl; W is O or (H, OH); X, Y and Z are independently, selected from:(a) hydrogen, (b) C₁₋₇ alkyl, (c) C₂₋₆ alkenyl, (d) halogen, (e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶ and R⁷ are, independently selected from(i) hydrogen, or (ii) C₁₋₆ alkyl unsubstituted or substituted with phenyl, and m is 0 to 2, (f) --CN, (g) --CHO, (h) --CF₃, (i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, or phenyl, (j) --SOR⁸, wherein R⁸ is as defined above, (k) --SO₂ R⁸, wherein R⁸ is as defined above, (l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, (m) R⁹ O(CH₂)_(m) - wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃ alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above, (n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or taken together form an ethyl or propyl bridge, (o) ##STR52## wherein R⁹ and m are as defined above, and (p) ##STR53## wherein R⁹ and m are as defined above, and (q) -OR¹¹ ; or any two of adjacent X, Y and Z can be joined to form a ring selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and n is 1 or
 2. 4. The compound of claim 1 wherein:R¹ and R² are independently selected from:(1) hydrogen; (2) C₁₋₁₀ alkyl; (3) substituted C₁₋₁₀ alkyl in which one or more substituent(s) is(are) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ -alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C₁₋₆ alkyl, (g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from(i) hydrogen, (ii) C₁₋₁₀ alkyl unsubstituted or substituted with one or more of the substituent(s) selected from:(a') phenyl, which is unsubstituted or substituted with X, Y and Z, (b') --OH, (c') C₁₋₆ alkoxy, (d') --CO₂ H, (e') --CO₂ --C₁₋₆ alkyl, (f') --C₃₋₇ cycloalkyl, and (g') --OR¹¹, (iii)C₃₋₁₀ alkenyl unsubstituted or substituted with one or more of the substituent(s) selected from:(a') phenyl, which is unsubstituted or substituted with X, Y and Z, (b') --OH, (c') C₁₋₆ alkoxy, (d') --CO₂ H, (e') --CO₂ --C₁₋₆ alkyl, (f') --C₃₋₇ cycloalkyl, and (g') --OR¹¹, (iv)or where R⁶ and R⁷ and the N to which they are attached can form a 3-7-membered saturated heterocyclic ring, unsubstituted or substituted with C₁₋₆ alkyl or phenyl, the ring being selected from the group consisting of: aziridine, morpholine, thiomorpholine, thiomorpholine-oxide, thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine, (h) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ is as defined above, (i) --NR⁶ CO₂ --C₁₋₆ alkyl-R⁷, (j) --NR⁶ CONR⁶ R⁷, (k) --OCONR⁶ R⁷, (l) --COOR⁶, (m) --CHO, (n) phenyl, (o) substituted phenyl in which the substituents are X, Y and Z, (p) phenyloxy, (q) substituted phenyloxy in which the substitutents are X, Y and Z, (r) 1- or 2- naphthyl, (s) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (t) biphenyl (u) substituted biphenyl in which the substituents are X, Y and Z; (v) --OR¹¹, and (w) --S(O)_(p) --C₁₋₆ alkyl; (4) C₃₋₁₀ alkenyl; (5) substituted C₃₋₁₀ alkenyl in which one or more substituent(s) is(are) selected from:(a) hydroxy, (b) oxo, (c) c₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C₁₋₆ alkyl, (g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above (h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above, (i) --COOR⁶, wherein R⁶ is as defined above, (j) --CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substitutents are X, Y and Z, (q) --OR¹¹, and (r) --S(O)_(p) --C₁₋₆ alkyl; (6) C₃₋₁₀ alkynyl; (7) substituted C₃₋₁₀ alkynyl in which one or more substituent(s) is(are) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenyl are X, Y and Z, (f) --OCO--C₁₋₆ alkyl, (g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, (h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above, (i) --COOR⁶, wherein R⁶ is as defined above, (j) --CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, and (q) --OR¹¹ ; with the proviso that R¹ and R² are not simultaneously hydrogen, methyl or combinations thereof; R³ is hydrogen, hydroxy, --OR¹¹ or C₁₋₆ alkoxy; R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond; R⁵ is methyl, ethyl, propyl or allyl; R¹¹ is selected from:(a) --PO(OH))O⁻ M⁺, wherein M⁺ is a positively charged inorganic or organic counterion, selected form the group consisting of: ammonium, sodium, lithium, potassium, calcium, magnesium, dicyclohexylamine, N-methyl-D-glucamine, arginine and lysine, (b) --SO₃ ⁻ M⁺, (c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and (d) --CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from:(i) hydroxy, (ii) C₁₋₆ alkoxy, (iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:(a') hydrogen, and (b') C₁₋₆ alkyl, (iv) --COOR⁶, wherein R⁶ is as defined above, (v) phenyl, (vi) substituted phenyl in which the substituents are X, Y and Z, (vii) --SH, and (viii) --S--C₁₋₆ alkyl; W is O or (H, OH); X, Y and Z independently are selected from:(a) hydrogen, (b) C₁₋₇ alkyl, (c) C₂₋₆ alkenyl, (d) halogen, (e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, and m is 0 to 2, (f) --CN, (g) --CHO, (h) --CF₃, (i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, or phenyl, (j) --SOR⁸, wherein R⁸ is as defined above, (k) --SO₂ R⁸, wherein R⁸ is as defined above, (l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, (m) R⁹ O(CH₂)_(m) - wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃ alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above, (n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or taken together form an ethyl or propyl bridge, (o) ##STR54## wherein R⁹ and m are as defined above, and (p) ##STR55## wherein R⁹ and m are as defined above, and (q) --OR¹¹ ; or any two of adjacent X, Y and Z can be joined to form a ring selected from the gorup consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and n is 1 or
 2. 5. A compound which is selected from the group consisting of:17-ethyl-1,14-dihydroxy-12-[2'-(4"-phenyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-phenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-phenyloxy-3"-hydroxycyclohexyl)-1"-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-chlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-methylphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,-25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone. 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-phenoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-phenoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-phenoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,-25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-1-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(naphth-1-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-1-yloxy) -3"-hydroxycylohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(napth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-methoxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-methoxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-methoxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methylthiophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dimethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(3'"-methoxyphenyloxy)-4"-hydroxycyclhexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricylo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4- azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16- tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dichlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(phenanthr-9-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-methylenedioxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'",3'"-dihydrobenzofuran-5-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-allyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-hydroxy-12-[2'-(4"-(4"'-dimethylamino)phenyloxy-3"-hdyroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]-octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-hydroxy-12-[2'-(4"-hydroxy-3"-(4"'-dimethylamino)phenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04,9]-octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1'",4'"-benzodioxane-6-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo]22.1.0⁴,9 ]octacos-18-ene-2,3,-10,16-tetraone; and 17-ethyl-1,2,14-trihydroxy-12-[2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-3,10,16-trione. P
 6. A compound which is selected from the group consisting of:17-ethyl-1,14-dihydroxy-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-butynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-phenyl propyloxycycylohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-allyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-allyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-sec-butenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(trans-2'"-butenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(trans-2'"-butenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-2'-(3"-hydroxy-4"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-cinnamyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴.9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-sec-butenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricylo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(2'"-(4"-(2'"-butynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[2.3.1.0⁴,9 ]octacos-18 -ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-allyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3"-allyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3"-hydroxy-4"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-(trans-2'"-butenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3"-(trans-2'"-butenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3"-hydroxy-4"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 9 octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-hydroxy-3"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3"-hydroxy-4"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-hydroxy-3"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3"-cinnamyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-sec-phenethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-methylcinnamyloxy) -3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methyl-2'",-4'"-hexadienyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3-10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(p-methoxycinnamyloxy)-3 "-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-methylenedioxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo]22.3.1.0⁴,9 ]-octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'",4'"-dimethyl-2'"-trans-pentenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-cyclohexyl-2'"-trans-propenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-p-chlorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-p-bromocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-p-fluorophenylpropyloxycylohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 0 octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3",4"-diallyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(3",4"-dipropyloxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatircyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16, -tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-benzyloxymethyoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-napth-2-yloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(ethoxycarbomethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,15-dimethoxy-13,19,21,17-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-hydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(3""-methoxyphenyl)-2'''-oxo-ethyloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(2'''-(3""-methoxyphenyl)-2'''-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14dihydroxy-12-[2'-(4"-(2'''-(3""-hydroxyphenyl) -2'''-oxo-ethyloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(4""-methoxyphenyl)-2'''-oxo-ethyloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-(2'''-(4""-methoxyphenyl) -2'''-oxo-ethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(4""-methoxyphenyl) -2'''-oxo-ethyloxy)-3"-hydroxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(3"", 5""-dimethoxyphenyl) -2'''-oxo-ethyloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(2'''-(3"", 5""-dimethoxyphenyl) -2'''-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(3"",5""-dimethoxyphenyl) -2'''-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(3"",5""-difluorophenyl) -2'''oxo-ethyloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(2'''-(3"",5""-didifluorophenyl -2'''-oxo-ethyloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 ]octacos-18-ene2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"(2'''-(3"",5""-difluorophenyl)-2'''-oxo-ethyloxy)-3"-hydroxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"(2'''-(4""-hydroxyphenyl)-2'''-oxo-ethyloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(2'''-(4""-hydroxyphenyl)-2'''-oxo-ethyloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(4""-hydroxphenyl) -2'''-oxo-ethyloxy)-3"-hydroxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-phenyl-2'''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(2'''-phenyl-2'''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo]22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-phenyl-2'''-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(3""-methoxyphenyl)-2'''-hydroxyethyloxy) -3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(2'''-(3""-methoxyphenyl) -2'''-hydroxyethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(3""-methoxyphenyl)-2'''-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methyvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(3"", 5""-dimethoxyphenyl)-2'''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19, 21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(2'''-(3"",5""-dimethoxyphenyl)-2'''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2''∝-(3"",5""-dimethoxyphenyl)-2'''-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(3"",5""-difluorophenyl)-2'''hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-enen-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(2'''-(3"",5""-difluorophenyl-2'''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1 '-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.2.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(3"",5""-difluorophenyl)-2'''-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(4""-hydroxyphenyl)-2'''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-(2'''-(4""-hydroxyphenyl)-2'''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(2'''-(4""-hydroxyphenyl)-2'''-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-fluorocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3''',5'''-difluorocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10, 16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-nitrocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'''-phenyl-2'"-propynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-phenyl-2'''-propenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(p-hydroxyphenpropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxycinnamyloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-hydroxymethylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxycinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3''',5'''-difluorocinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(p-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carbomethoxybenzyloxy)-3"-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-isopropylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-butylcarboxamidobenzyloxy)-3"-methoxycyclohexy)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-acetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.2.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(N-phenylacetamidoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(N-benzylacetamidoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[2.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-carboxymethyl-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(N-benzylamidoxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(N-methyltyrosine)amidoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(m-methylphenyl)-2'''-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(p-methylphenyl)-2'''-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-phenyl-2'''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(m-methylphenyl)-2'''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-(m-ethylphenyl)-2'''-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-phenylethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-phenyl-2'''-acetoxyethyloxy)-3"-methoxycyclohexyl)-1"-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(2'''-morpholinoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-ylmethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4''',5'''-methylenedioxybenzyloxy)-3"-methoxycyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-N,N,-dimethylaminophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetriamethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-(2""-dioxolanylphenyloxy) -3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-formylphenyloxy)-3"-methoxycyclohexyl)-1"-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-carboxyphenyloxy) -3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",4'"-dimethoxyphenyloxy) -3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-trifluoromethylphenyloxy) -3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'",5'"-bis (trifluoromethyl)phenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-(4'"-methylphenyloxy) -3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-methylphenyloxy) cyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy) -3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-hydroxyphenyloxy) cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-(4'"-hydroxymethylphenyloxy) -3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]-octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-hydroxymethylphenyloxy) cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene -2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"hydroxy-3"-(4'"-formylphenyloxy) cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-(4'"-N,N-dimethylaminiphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo ]22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-N,N-dimethylaminophenyloxy) cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-phenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo ]22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-hydroxy-3"-phenyloxy) cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo ]22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy) -3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone and; 17-ethyl-1hydroxy-12-[2'-(4"-hydroxy-3"-(4'"-methoxyphenyloxy) cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1hydroxy-12-[2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone; and 17-ethyl-1hydroxy-12-[2'-(4"-hydroxy-3"-(3'"-methoxyphenyloxy) cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone.
 7. A compound which is: ##STR56## wherein R¹ and R² are selected from the following combinations:

    ______________________________________                                         R.sup.1              R.sup.2                                                   ______________________________________                                         a)                                                                                  ##STR57##           CH.sub.3                                              b)                                                                                  ##STR58##           H                                                     c)                                                                                  ##STR59##           CH.sub.3                                              d)                                                                                  ##STR60##           CH.sub.3                                              e)                                                                                  ##STR61##           H                                                     f)                                                                                  ##STR62##           H                                                     g)                                                                                  ##STR63##           CH.sub.3                                              h)                                                                                  ##STR64##           CH.sub.3                                              i)                                                                                  ##STR65##           H                                                     j)  H                                                                                                    ##STR66##                                            k)  H                                                                                                    ##STR67##                                            l)  H                                                                                                    ##STR68##                                            m)                                                                                  ##STR69##           CH.sub.3                                              n)                                                                                  ##STR70##           H                                                     o)                                                                                  ##STR71##           CH.sub.3                                              p)                                                                                  ##STR72##           CH.sub.3                                              q)                                                                                  ##STR73##           H                                                     r)                                                                                  ##STR74##           H.                                                    ______________________________________                                    


8. The compound of claim 7 which is: ##STR75##
 9. The compound of claim 7 which is: ##STR76##
 10. A compound which is: ##STR77## wherein R¹ and R² are selected from the following combinations:

    ______________________________________                                                R.sup.1       R.sup.2                                                   ______________________________________                                         a)                                                                                       ##STR78##      CH.sub.3                                              b)                                                                                       ##STR79##      H                                                     c)                                                                                       ##STR80##      CH.sub.3                                              d)                                                                                       ##STR81##      H                                                     e)                                                                                       ##STR82##      CH.sub.3                                              f)                                                                                       ##STR83##      H                                                     g)                                                                                       ##STR84##      CH.sub.3                                              h)                                                                                       ##STR85##      CH.sub.3                                              i)                                                                                       ##STR86##      H                                                     j)                                                                                       ##STR87##      CH.sub.3                                              k)                                                                                       ##STR88##      H                                                     l)                                                                                       ##STR89##      CH.sub.3                                              m)                                                                                       ##STR90##      H                                                     n)                                                                                       ##STR91##      CH.sub.3                                              o)                                                                                       ##STR92##      H                                                     p)                                                                                       ##STR93##      CH.sub.3                                              q)                                                                                       ##STR94##      H                                                     r)                                                                                       ##STR95##      CH.sub.3                                              s)                                                                                       ##STR96##      H                                                     t)                                                                                       ##STR97##      CH.sub.3                                              u)                                                                                       ##STR98##      H                                                     v)                                                                                       ##STR99##      CH.sub.3                                              w)                                                                                       ##STR100##     H                                                     x)                                                                                       ##STR101##     CH.sub.3                                              y)                                                                                       ##STR102##     H                                                     z)                                                                                       ##STR103##     CH.sub.3                                              aa)                                                                                      ##STR104##     CH.sub.3                                              bb)                                                                                      ##STR105##     CH.sub.3                                              cc)                                                                                      ##STR106##     CH.sub.3                                              dd)                                                                                      ##STR107##     CH.sub.3                                              ee)                                                                                      ##STR108##     CH.sub.3                                              ff)                                                                                      ##STR109##     CH.sub.3                                              gg)                                                                                      ##STR110##     CH.sub.3                                              hh)      H                                                                                               ##STR111##                                           ii)                                                                                      ##STR112##     CH.sub.3                                              jj)                                                                                      ##STR113##     H                                                     kk)      H                                                                                               ##STR114##                                           ______________________________________                                    


11. The compound of claim 10 which is: ##STR115##
 12. The compound of claim 10 which is: ##STR116##
 13. The compound of claim 10 which is: ##STR117##
 14. The compound of claim 10 which is: ##STR118##
 15. The compound of claim 10 which is: ##STR119## 